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Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE−/- mice via miR-let7 mediated infiltration and polarization of M2 macrophage
Abstract
Atherosclerosis is a chronic inflammatory disease of the vasculature. Exosomes derived from mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects; however, the MSCs-exosomes administration on atherosclerosis was unknown. Here, our ApoE −/- mice were fed a high-fat diet and received intravenous injections of exosomes from MSCs for 12 weeks. After tail-vein injection, MSCs-exosomes were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. MSCs-exosomes treatment decreased the atherosclerotic plaque area of ApoE −/- mice and greatly reduced the infiltration of macrophages in the plaque, associating induced macrophage polarization towards M2. In vitro, MSCs-exosomes treatment markedly inhibited LPS-induced M1 markers expression, while increased M2 markers expression in macrophages. Moreover, miR-let7 family was found to be highly enriched in MSCs-exosomes. Endogenous miR-let7 expression was found in the aortic root of ApoE −/- mice, and MSCs-exosomes treatment further up-regulated miR-let7 levels. In addition, inhibition of miR-let7 in U937 cells significantly inhibited the migration and M2 polarization via IGF2BP1 and HMGA2 pathway respectively in vitro. Our study demonstrates that MSCs-exosomes ameliorated atherosclerosis in ApoE −/- and promoted M2 macrophage polarization in the plaque through miR-let7/HMGA2/NF-κB pathway. In addition, MSCs-exosomes suppressed macrophage infiltration via miR-let7/IGF2BP1/PTEN pathway in the plaque. This finding extends our knowledge on MSCs-exosomes affect inflammation in atherosclerosis plaque and provides a potential method to prevent the atherosclerosis. Exosomes from MSCs hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases.
... Atherosclerosis mADMSC EC -MAPK and NF-κB pathways [19] hBMMSC SMC miR-221 NAT1 [20] rBMMSC Macrophage -SLC2a1, STAT3/RAC1, and CD300a pathways; CD36-mediated pathway [21] mBMMSC Macrophage miR-let7 HMGA2/NF-kB pathway; IGF2BP1/PTEN pathway [22] mBMMSC Macrophage miR-223 NLRP3 [23] Aneurysm UCMSC Macrophage, SMC miR-147 HMGB-1 and IL-17 [24] hBMMSC -miR-23b-3p PI3k/Akt/NF-κB pathway, KLF5 [25] ...
... AS, characterized by the formation of fibrofatty lesions in the arterial wall, is a chronic inflammatory vascular disease that is the major cause of cardiovascular diseases and stroke. The accumulation of certain plasma lipoproteins, the activation of ECs, and the MSC-EVs are capable of ameliorating AS by modifying vascular cells to a more normal phenotype and regulating the inflammatory response [19][20][21][22][23]. For example, adiposederived MSC (ADMSC)-released EV treatment decreased the expression levels of cell adhesion molecules, including vascular cell adhesion protein-1, intercellular adhesion molecule (ICAM)-1, and E-selectin, on the surface of ECs, which were prone to suppress subsequent monocyte adhesion and macrophage accumulation in the vascular walls and finally ameliorated AS in Ldlr −/− mice [19]. ...
... However, MSCderived exosomes can restore efferocytosis function and prevent foam cell formation [21]. In addition, MSC-EVs can decrease inflammation by promoting the polarization of M2 macrophages or inhibiting the activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome which can lead to macrophage pyroptosis [22,23]. ...
Extracellular vesicles (EVs), as part of the cellular secretome, have emerged as essential cell–cell communication regulators in multiple physiological and pathological processes. Previous studies have widely reported that mesenchymal stromal cell-derived EVs (MSC-EVs) have potential therapeutic applications in ischemic diseases or regenerative medicine by accelerating angiogenesis. MSC-EVs also exert beneficial effects on other vasculopathies, including atherosclerosis, aneurysm, vascular restenosis, vascular calcification, vascular leakage, pulmonary hypertension, and diabetic retinopathy. Consequently, the potential of MSC-EVs in regulating vascular homeostasis is attracting increasing interest. In addition to native or naked MSC-EVs, modified MSC-EVs and appropriate biomaterials for delivering MSC-EVs can be introduced to this area to further promote their therapeutic applications. Herein, we outline the functional roles of MSC-EVs in different vasculopathies and angiogenesis to elucidate how MSC-EVs contribute to maintaining vascular system homeostasis. We also discuss the current strategies to optimize their therapeutic effects, which depend on the superior bioactivity, high yield, efficient delivery, and controlled release of MSC-EVs to the desired regions, as well as the challenges that need to be overcome to allow their broad clinical translation.
... Paracrine secretion is another regulatory pathway for MSCs, and exosomes are one of the important paracrine substances that are thought to regulate cellular function through a third signaling pathway. 75 Exosomes contain a large number of functional RNAs and the most common functional RNAs in exosomes are microRNAs (miRNAs), which regulate M1 and M2 macrophage polarization at the post-transcriptional level by targeting various transcription factors. 75,76 Reports in the literature have shown that MSCs under hypoxic conditions secrete a large number of exosomes-containing proteins and miRNAs (e.g., miR-223, miR-146b, miR126 and miR-199a) that are involved in different stages of the M2 macrophage polarization and healing process. ...
... 75 Exosomes contain a large number of functional RNAs and the most common functional RNAs in exosomes are microRNAs (miRNAs), which regulate M1 and M2 macrophage polarization at the post-transcriptional level by targeting various transcription factors. 75,76 Reports in the literature have shown that MSCs under hypoxic conditions secrete a large number of exosomes-containing proteins and miRNAs (e.g., miR-223, miR-146b, miR126 and miR-199a) that are involved in different stages of the M2 macrophage polarization and healing process. 77 miR-223, as a novel regulator of macrophage polarization inhibits the classical pro-inflammatory pathway, enhances macrophage polarization towards M2 macrophages and reduces the inflammatory response and insulin resistance by inhibiting Pknox1. ...
Tendinopathies are chronic diseases of an unknown etiology and associated with inflammation. Mesenchymal stem cells (MSCs) have emerged as a viable therapeutic option to combat the pathological progression of tendinopathies, not only because of their potential for multidirectional differentiation and self-renewal, but also their excellent immunomodulatory properties. The immunomodulatory effects of MSCs are increasingly being recognized as playing a crucial role in the treatment of tendinopathies, with MSCs being pivotal in regulating the inflammatory microenvironment by modulating the immune response, ultimately contributing to improved tissue repair. This review will discuss the current knowledge regarding the application of MSCs in tendinopathy treatments through the modulation of the immune response.
... MSCs Reduce migration and prevent maturation of DCs [42] miR-let7 MSCs Decrease the macrophage infiltration in the plaque [46] miR-155 M1 Reduces the MSC osteogenic differentiation [47] miR-378 M2 Increase MSC osteoinductive gene expression [47] miR-21-5p M Enhance fibrogenesis in tendons [48] miR-222 Breast cancer cell Macrophage polarization to M2 and tumor progression [158] miR-23a HCC Suppress T-cell function, and increase phosphorylated AKT and PD-L1 expression in macrophages [53] miRNA-335 T cells Downregulates translation of SOX-4 mRNA in APCs [62] mmu-miR-20a-5p mmu-miR-25-3p mmu-miR-155-3p ...
... Mesenchymal stem cells (MSCs)-derived exosomes have the ability to improve atherosclerosis in APOE −/− mice by decreasing the macrophage infiltration in the plaque through the miR-let7/ IGF2BP1/ PTEN pathway. Further, MSCs-exosomes increased M2 macrophage polarization in the plaque via the miR-let7/ HMGA2/NF-κB pathway [46]. It was found that miR-155 in M1 macrophage EV reduces the MSC osteogenic differentiation, while miR-378 in M2 macrophage EV increased MSC osteoinductive gene expression. ...
Extracellular communication, in other words, crosstalk between cells, has a pivotal role in the survival of an organism. This communication occurs by different methods, one of which is extracellular vesicles. Exosomes, which are small lipid extracellular vesicles, have recently been discovered to have a role in signal transduction between cells inside the body. These vesicles contain important bioactive molecules including lipids, proteins, DNA, mRNA, and noncoding RNAs such as microRNAs (miRNAs). Exosomes are secreted by all cells including immune cells (macrophages, lymphocytes, granulocytes, dendritic cells, mast cells) and tumor cells. The tumor microenvironment (TME) represents a complex network that supports the growth of tumor cells. This microenvironment encompasses tumor cells themselves, the extracellular matrix, fibroblasts, endothelial cells, blood vessels, immune cells, and non-cellular components such as exosomes and cytokines. This review aims to provide insights into the latest discoveries concerning how the immune system communicates internally and with other cell types, with a specific focus on research involving exosomal miRNAs in macrophages, dendritic cells, B lymphocytes, and T lymphocytes. Additionally, we will explore the role of exosomal miRNA in the TME and the immunomodulatory effect.
... This treatment decreased the area of atherosclerotic plaque, reduced macrophage infiltration in the plaque and promoted macrophage polarisation towards M2 phenotype. Further research has defined miR-let7 as the major enriched miRNA in MSC-exosomes, which acted through High Mobility Group AT-Hook 2 (HMGA2)/NF-κB pathway to promote M2 macrophage polarisation and through IGF2BP1/PTEN pathway to suppress macrophage infiltration in the plaque, thus alleviating atherosclerosis in ApoE -/mice [90]. ...
Atherosclerotic cardiovascular disease (ASCVD) is an advanced chronic inflammatory disease and the leading cause of death worldwide. The pathological development of ASCVD begins with atherosclerosis, characterised by a pathological remodelling of the arterial wall, lipid accumulation and build-up of atheromatous plaque. As the disease advances, it narrows the vascular lumen and limits the blood, leading to ischaemic necrosis in coronary arteries. Exosomes are nano-sized lipid vesicles of different origins that can carry many bioactive molecules from their parental cells, thus playing an important role in intercellular communication. The roles of exosomes in atherosclerosis have recently been intensively studied, advancing our understanding of the underlying molecular mechanisms. In this review, we briefly introduce exosome biology and then focus on the roles of exosomes of different cellular origins in atherosclerosis development and progression, functional significance of their cargoes and physiological impact on recipient cells. Studies have demonstrated that exosomes originating from endothelial cells, vascular smooth muscle cells, macrophages, dendritic cells, platelets, stem cells, adipose tissue and other sources play an important role in the atherosclerosis development and progression by affecting cholesterol transport, inflammatory, apoptotic and other aspects of the recipient cells' metabolism. MicroRNAs are considered the most significant type of bioactive molecules transported by exosomes and involved in ASCVD development. Finally, we review the current achievements and limitations associated with the use of exosomes for the diagnosis and treatment of ASCVD.
... Одним из актуальных направлений в области биомедицины является исследование возможности применения экзосом в диагностическом и дифференциально-диагностическом аспектах, а также в качестве средств доставки терапевтических агентов. В дерматологии использование экзосом может быть актуальным как при совершенствовании местных способов терапии, так и в диагностике хронических дерматозов [1][2][3][4][5]. ...
Hair loss, cicatricial skin changes and chronic immune-mediated dermatoses are a serious social and medical problem, as they can lead to social maladjustment of a person due to changes in appearance, constant pain and itching. At the same time, the existing methods of their diagnosis and complex treatment need to be improved. This review discusses novel promising approaches to the diagnosis and treatment of chronic immune-mediated dermatosis, alopecia, and skin wounds based on exosomes, extracellular vesicles secreted by cells that have specificity and the ability to penetrate into other cells and transfer their contents represented by various regulatory molecules to them. The review collects available information on the origin and exosomes cargo, reveals their diagnostic potential, and provides information on the therapeutic potential of these stem cell-derived vesicles.
... 28,29 Besides, MSC-derived exosomes also reduced inflammation and exerted immunomodulatory effects, ultimately preventing the formation of unstable plaques. 30,31 Hence, an in-depth comprehension of MSC-derived exosomes will contribute to the development of innovative therapeutic approaches for atherosclerosis. Despite the therapeutic potential of MSC-derived exosomes, their clinical translation is limited by several challenges, such as the efficiency of production, the complexities of exosomal isolation and purification, and the precision of targeted delivery to recipient cells. ...
Purpose
Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis.
Methods
To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs.
Results
Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE−/− mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1.
Conclusion
This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.
... [79] Furthermore, it was reported that hUC-MSCs-exosomes' immunosuppressive capabilities alleviate inflammation, help in diabetic cutaneous conditions, enhance wound healing and burn inflammations, and exosomes from mouse BM-MSCs (mBM-MSCs) regress osteosclerosis, and decrease atherosclerotic plaques, myocardial ischemia-reperfusion damage, and infarct size. [80][81][82] Exosomes derived from hBM-MSCs are therapeutically effective by inducing M2 macrophages in intestinal bowel disease in mice and are also useful in improving motor skills in a mouse model of multiple sclerosis. [83] On top of that, exosomes derived from ADSCs depending on the species from which they are derived can demonstrate various effects including, showing a decrease in cardiac damage, fibrosis, and apoptosis when derived from rats; increasing the expression of M2 macrophages when derived from humans; increasing the polarization of M2 macrophages in obese mice when derived from mice; and are effective in the treatment of autoimmune type 1 diabetes mellitus. ...
Extracellular vesicles (EVs) are released by all cells and have a variety of physiological functions. Microvesicles (MV), exosomes, oncosomes, and apoptotic bodies, are the four forms of EVs. Exosomes are spherical EV with an endocytic double-layered lipid membrane. As for their identification, it's based on isolation methods, cell type, and cell surface markers. Moreover, their functions differ according to the cell from which they are obtained. They are involved in the immune system, neural communication, drug delivery, and many other processes. Another type of EV is MVs, which are a diverse collection of vesicles formed by the outward budding of the plasma membrane. Differentiating these two types of EVs is mostly based on the process of biogenesis. MVs play a variety of pathological and physiological roles. MVs were hypothesized to have a role in the immunomodulatory function of mesenchymal stem cells (MSCs). Following that, it was discovered that MVs secreted by damaged cells send precise signals to MSCs. Given their physiological contact with the target cell, MVs are regarded to be therapeutic targets in cancer treatment. This chapter provides information about exosomes and microvesicles, which are extracellular vesicles.
... At the same time, they also inhibited the secretion of pro-inflammatory cytokines while augmenting the synthesis of anti-inflammatory cytokines. In addition, MSC-EVs can inhibit the activity of M1 macrophages and promote their polarization to M2 macrophages through the miR-let-7/IGF2BP1/PTEN signaling [87]. ...
Mesenchymal stem cells (MSCs) are a type of stromal cells characterized by their properties of self-renewal and multi-lineage differentiation, which make them prominent in regenerative medicine. MSCs have shown significant potential for the treatment of various diseases, primarily through the paracrine effects mediated by soluble factors, specifically extracellular vesicles (EVs). MSC-EVs play a crucial role in intercellular communication by transferring various bioactive substances, including proteins, RNA, DNA, and lipids, highlighting the contribution of MSC-EVs in regulating cancer development and progression. Remarkably, increasing evidence indicates the association between MSC-EVs and resistance to various types of cancer treatments, including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and endocrinotherapy. In this review, we provide an overview of the recent advancements in the biogenesis, isolation, and characterization of MSC-EVs, with an emphasis on their functions in cancer therapy resistance. The clinical applications and future prospects of MSC-EVs for mitigating cancer therapy resistance and enhancing drug delivery are also discussed. Elucidating the role and mechanism of MSC-EVs in the development of treatment resistance in cancer, as well as evaluating the clinical significance of MSC-EVs, is crucial for advancing our understanding of tumor biology. Meanwhile, inform the development of effective treatment strategies for cancer patients in the future.
... Based on the findings of this study, MSC-exosomes may be an effective strategy for preventing atherosclerosis as they may significantly reduce inflammation in atherosclerosis plaques. [102] Cochain et al. also studied the interaction between exosomes and macrophages. Numerous functional [127] miR-208 Diagnosis and prognosis Be increased in patients with DCM In vivo study Human study [127] miR-499 Diagnosis and prognosis Be increased in patients with DCM In vivo study Human study [127] miR-19b-3p Diagnosis and prognosis Positively correlate with myocardial status In vivo study [128] miR-181b-5p Diagnosis and prognosis Positively correlate with myocardial status In vivo study [128] miR-126 Diagnosis and prognosis Be increased in patients with DCM In vivo study [129] miR-320 Diagnosis and prognosis Be increased in patients with DCM In vivo study [129] miR-19a Treatment Preserve cardiac contractile function and reduce infarct size In vitro study [96] miR-29b Treatment Alleviate fibrosis and cardiomyocyte uncoupling in DCM In vivo study [130] miR-455 Treatment Alleviate fibrosis and cardiomyocyte uncoupling in DCM In vivo study [130] miR-26a Treatment Prevent CKD-induced muscle wasting and attenuate cardiomyopathy In vivo study [133] miR-155 Treatment Mediate cardiomyocyte pyroptosis in uremic hearts by downregulating FoxO3a protein expression In vivo study [134] miR-122 Treatment Improve cardiac remodeling and metabolic profiles Human study [136] miR-29a Treatment Regulate cardiac parameters in human subjects Human study [137] phenotypes of macrophages were found in atherosclerotic plaques, which responded to the microenvironment and played various roles in vascular inflammation and atherosclerosis. ...
Microvesicles known as exosomes have a diameter of 40 to 160 nm and are derived from small endosomal membranes. Exosomes have attracted increasing attention over the past ten years in part because they are functional vehicles that can deliver a variety of lipids, proteins, and nucleic acids to the target cells they encounter. Because of this function, exosomes may be used for the diagnosis, prognosis and treatment of many diseases. All throughout the world, cardiovascular diseases (CVDs) continue to be a significant cause of death. Because exosomes are mediators of communication between cells, which contribute to many physiological and pathological aspects, they may aid in improving CVD therapies as biomarkers for diagnosing and predicting CVDs. Many studies demonstrated that exosomes are associated with CVDs, such as coronary artery disease, heart failure, cardiomyopathy and atrial fibrillation. Exosomes participate in the progression or inhibition of these diseases mainly through the contents they deliver. However, the application of exosomes in diferent CVDs is not very mature. So further research is needed in this field.
... For instance, in a mouse model of atherosclerosis, BMSC-derived exosomes induced polarization of macrophages from pro-inflammatory phenotype M1 to anti-inflammatory phenotype M2 via miR-let7, which attenuated disease progression. 150 Similarly, MSC-derived exosomes have been shown to induce synovial macrophage polarization from M1 to M2, thereby suppressing inflammation and slowing the progression of OA. 151 In addition, MSC-derived exosomes can inhibit immune cells such as B-cell proliferation, 152 T-cell differentiation and proliferation, 153 and DC cell maturation, 154 exerting immunosuppressive capacity. Hence, MSC-derived exosomes possess great potential for the treatment of inflammatory diseases. ...
Exosomes, as natural nanocarriers, characterized with low immunogenicity, non-cytotoxicity and targeted delivery capability, which have advantages over synthetic nanocarriers. Recently, exosomes have shown great potential as diagnostic markers for diseases and are also considered as a promising cell-free therapy. Engineered exosomes have significantly enhanced the efficacy and precision of delivering therapeutic agents, and are currently being extensively employed in targeted therapeutic investigations for various ailments, including oncology, inflammatory disorders, and degenerative conditions. Particularly, engineered exosomes enable therapeutic agent loading, targeted modification, evasion of MPS phagocytosis, intelligent control, and bioimaging, and have been developed as multifunctional nano-delivery platforms in recent years. The utilization of bioactive scaffolds that are loaded with exosome delivery has been shown to substantially augment retention, extend exosome release, and enhance efficacy. This approach has advanced from conventional hydrogels to nanocomposite hydrogels, nanofiber hydrogels, and 3D printing, resulting in superior physical and biological properties that effectively address the limitations of natural scaffolds. Additionally, plant-derived exosomes, which can participate in gut flora remodeling via oral administration, are considered as an ideal delivery platform for the treatment of intestinal diseases. Consequently, there is great interest in exosomes and exosomes as nanocarriers for therapeutic and diagnostic applications. This comprehensive review provides an overview of the biogenesis, composition, and isolation methods of exosomes. Additionally, it examines the pathological and diagnostic mechanisms of exosomes in various diseases, including tumors, degenerative disorders, and inflammatory conditions. Furthermore, this review highlights the significance of gut microbial-derived exosomes. Strategies and specific applications of engineered exosomes and bioactive scaffold-loaded exosome delivery are further summarized, especially some new techniques such as large-scale loading technique, macromolecular loading technique, development of multifunctional nano-delivery platforms and nano-scaffold-loaded exosome delivery. The potential benefits of using plant-derived exosomes for the treatment of gut-related diseases are also discussed. Additionally, the challenges, opportunities, and prospects of exosome-based nanocarriers for disease diagnosis and treatment are summarized from both preclinical and clinical viewpoints.
... Chen, Zhou, Zhang, & Hu, 2021) and let 7 family (J. Li et al., 2019) are also involved as therapeutic drugs for AS, which fully demonstrates the great potential of MSC-derived exosomes as therapeutic agents. In parallel, there are many other sources of exosomes used in AS. ...
Atherosclerosis (AS) is considered to be one of the major causes of cardiovascular disease. Its pathological microenvironment is characterized by increased production of reactive oxygen species, lipid oxides, and excessive inflammatory factors, which accumulate at the monolayer endothelial cells in the vascular wall to form AS plaques. Therefore, intervention in the pathological microenvironment would be beneficial in delaying AS. Researchers have designed biomimetic nanomedicine (nanomedicine) with excellent biocompatibility and the ability to avoid being cleared by the immune system through different therapeutic strategies to achieve better therapeutic effects for the characteristics of AS. Biomimetic nanomedicine can further enhance delivery efficiency and improve treatment efficacy due to their good biocompatibility and ability to evade clearance by the immune system. Biomimetic nanomedicine based on therapeutic strategies such as neutralizing inflammatory factors, ROS scavengers, lipid clearance and integration of diagnosis and treatment are versatile approaches for effective treatment of AS. The review firstly summarizes the targeting therapeutic strategy of biomimetic nanomedicine for AS in recent 5 years. Biomimetic nanomedicine using cell membranes, proteins, and extracellular vesicles as carriers have been developed for AS.
... In addition, EVs can also regulate the polarization and infiltration of macrophages by transmitting miRNA. For example, miR-let7 related to bone marrow MSCs-Exo regulates the polarization and infiltration of M2 macrophages by targeting HMGA2 and IGF2BP1, thus treating atherosclerosis [82]. In myocardial I/R injury, KLF2 overexpressed miR-24-3p in endothelial cell-derived EVs, which inhibited Ly6Chigh Mo/MФ migration by reducing CCR2 expression post-transcriptionally, thereby alleviating myocardial I/R injury in mice [83]. ...
Inflammatory bone disease is a general term for a series of diseases caused by chronic inflammation, which leads to the destruction of bone homeostasis, that is, the osteolytic activity of osteoclasts increases, and the osteogenic activity of osteoblasts decreases, leading to osteolysis. Macrophages are innate immune cell with plasticity, and their polarization is related to inflammatory bone diseases. The dynamic balance of macrophages between the M1 phenotype and the M2 phenotype affects the occurrence and development of diseases. In recent years, an increasing number of studies have shown that extracellular vesicles existing in the extracellular environment can act on macrophages, affecting the progress of inflammatory diseases. This process is realized by influencing the physiological activity or functional activity of macrophages, inducing macrophages to secrete cytokines, and playing an anti-inflammatory or pro-inflammatory role. In addition, by modifying and editing extracellular vesicles, the potential of targeting macrophages can be used to provide new ideas for developing new drug carriers for inflammatory bone diseases.
... In a spinal cord injury model, BM-MSC-EVs exerted neuroprotective effects by targeting interferon regulatory factor 5 (IRF5) expression in macrophages via miR-125a [122]. In a mouse model of atherosclerosis, miR-21a-5p from MSC-derived exosomes promoted macrophage polarization and reduced their infiltration within the atheroma by targeting KLF6 and ERK1/2 signaling pathways [123], while miR-let7 from MSC-EVs were shown to promote M2 macrophage polarization through miR-let7/HMGA2/NF-κB pathway, and suppress macrophage infiltration via miR-let7/IGF2BP1/PTEN pathway [124]. ...
Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the potential and emerging approaches for the treatment of kidney disease is mesenchymal stromal/stem cell (MSC) therapy, shown to have beneficial effects in preclinical studies. In addition, extracellular vesicles (EVs) released by MSCs became a potent cell-free therapy option in various preclinical models of kidney disease due to their regenerative, anti-inflammatory, and immunomodulatory properties. However, there are scarce clinical data available regarding the use of MSC-EVs in kidney pathologies. This review article provides an outline of the renoprotective effects of MSC-EVs in different preclinical models of kidney disease. It offers a comprehensive analysis of possible mechanisms of action of MSC-EVs with an emphasis on kidney disease. Finally, on the journey toward the implementation of MSC-EVs into clinical practice, we highlight the need to establish standardized methods for the characterization of an EV-based product and investigate the adequate dosing, safety, and efficacy of MSC-EVs application, as well as the development of suitable potency assays.
... There is also a continuous phenotype between them, and the subtype transition of macrophages plays a key role in the transition between the inflammatory and proliferative phases [39]. MSCs can mediate the polarization of macrophages in a variety of ways, and macrophages can respond to microenvironmental factors in tissues [40]. Conditioned medium after MSCs culture, which contains growth factors, cytokines, microRNA (miRNA), and other small molecular weight signal cues, have great regenerative and immunomodulatory potential [41]. ...
Background:
Human periodontal ligament stem cells (hPDLSCs) have a superior ability to promote the formation of new bones and achieve tissue regeneration. However, mesenchymal stem cells (MSCs) are placed in harsh environments after transplantation, and the hostile microenvironment reduces their stemness and hinders their therapeutic effects. Klotho is an antiaging protein that participates in the regulation of stress resistance. In our previous study, we demonstrated the protective ability of Klotho in hPDLSCs.
Methods:
A cranial bone defect model of rats was constructed, and the hPDLSCs with or without Klotho pretreatment were transplanted into the defects. Histochemical staining and micro-computed tomography were used to detect cell survival, osteogenesis, and immunoregulatory effects of hPDLSCs after transplantation. The in vitro capacity of hPDLSCs was measured by a macrophage polarization test and the inflammatory level of macrophages. Furthermore, we explored autophagy activity in hPDLSCs, which may be affected by Klotho to regulate cell homeostasis.
Results:
Pretreatment with the recombinant human Klotho protein improved cell survival after hPDLSC transplantation and enhanced their ability to promote bone regeneration. Furthermore, Klotho pretreatment can promote stem cell immunomodulatory effects in macrophages and modulate cell autophagy activity, in vivo and in vitro.
Conclusion:
These findings suggest that the Klotho protein protects hPDLSCs from stress after transplantation to maintain stem cell function via enhancing the immunomodulatory ability of hPDLSCs and inhibiting cell autophagy.
... Exosomes derived from MSCs contain high levels of a variety of miRNAs that inhibit AS plaque formation and a variety of proteins that inhibit inflammation and promote extracellular matrix synthesis (92). Specifically, MSCs-derived exosomes promote macrophage M2 polarization in AS plaques and inhibit macrophage infiltration, thereby reducing plaque volume (93). Adipose-derived MSCs secreted exosomes to inhibit miR-342-5p through protein phosphatase 1 regulatory subunit 12B, which effectively protected endothelial cells from AS (94). ...
Background:
Research on exosomes in metabolic diseases has been gaining attention, but a comprehensive and objective report on the current state of research is lacking. This study aimed to conduct a bibliometric analysis of publications on "exosomes in metabolic diseases" to analyze the current status and trends of research using visualization methods.
Methods:
The web of science core collection was searched for publications on exosomes in metabolic diseases from 2007 to 2022. Three software packages, VOSviewer, CiteSpace, and R package "bibliometrix" were used for the bibliometric analysis.
Results:
A total of 532 papers were analyzed, authored by 29,705 researchers from 46 countries/regions and 923 institutions, published in 310 academic journals. The number of publications related to exosomes in metabolic diseases is gradually increasing. China and the United States were the most productive countries, while Ciber Centro de Investigacion Biomedica en Red was the most active institution. The International Journal of Molecular Sciences published the most relevant studies, and Plos One received the most citations. Khalyfa, Abdelnaby published the most papers and Thery, C was the most cited. The ten most co-cited references were considered as the knowledge base. After analysis, the most common keywords were microRNAs, biomarkers, insulin resistance, expression, and obesity. Applying basic research related on exosomes in metabolic diseases to clinical diagnosis and treatment is a research hotspot and trend.
Conclusion:
This study provides a comprehensive summary of research trends and developments in exosomes in metabolic diseases through bibliometrics. The information points out the research frontiers and hot directions in recent years and will provide a reference for researchers in this field.
... In particular, MSC-derived EVs containing miR-let7 (EV-miR-let7) are capable of mitigating the development of AS. EV-miR-let7 can induce M2 polarization and attenuate macrophage infiltration in plaques through IGF2BP1/PTEN pathway [50] (Figure 1). Similarly, MSC-derived EV-miR-21a-5p promotes M2 polarization of macrophages and suppresses macrophage migration through targeting KLF6 and signalregulated-kinase-1/2 (ERK1/2), which ultimately alleviates the development of AS [31]. ...
Simple Summary
The role of exosomal non-coding RNA (ncRNA) in regulating macrophage polarization and the role of polarized macrophages as an important source of extracellular vesicles in cardiovascular diseases remains to be elucidated. In this review, we aim to summarize the role and molecular mechanisms of exosomal-ncRNA in regulating macrophage polarization and contributing to cardiovascular diseases. We also discuss the role of polarized macrophages and their derived extracellular vesicles as well as the therapeutic prospects of exosomal ncRNA in the treatment of cardiovascular diseases.
Abstract
Extracellular vesicles (EVs) or exosomes are nanosized extracellular particles that contain proteins, DNA, non-coding RNA (ncRNA) and other molecules, which are widely present in biofluids throughout the body. As a key mediator of intercellular communication, EVs transfer their cargoes to target cells and activate signaling transduction. Increasing evidence shows that ncRNA is involved in a variety of pathological and physiological processes through various pathways, particularly the inflammatory response. Macrophage, one of the body’s “gatekeepers”, plays a crucial role in inflammatory reactions. Generally, macrophages can be classified as pro-inflammatory type (M1) or anti-inflammatory type (M2) upon their phenotypes, a phenomenon termed macrophage polarization. Increasing evidence indicates that the polarization of macrophages plays important roles in the progression of cardiovascular diseases (CVD). However, the role of exosomal ncRNA in regulating macrophage polarization and the role of polarized macrophages as an important source of EV in CVD remains to be elucidated. In this review, we summarize the role and molecular mechanisms of exosomal-ncRNA in regulating macrophage polarization during CVD development, focusing on their cellular origins, functional cargo, and their detailed effects on macrophage polarization. We also discuss the role of polarized macrophages and their derived EV in CVD as well as the therapeutic prospects of exosomal ncRNA in the treatment of CVD.
... Atherosclerosis (AS) is a major risk factor for cardiovascular disease (CVD) [3], and lipid deposition and inflammatory effects are the main triggers for the development of AS. AS is a chronic inflammatory disease within the vascular system and is most likely to occur particularly in the arterial branches [4]. The pathogenic process of AS is divided into three stages [5], during the initiation phase, lipids gradually accumulate in the foam cells of the vessel wall. ...
Cardiovascular disease (CVD) has a high incidence and low cure rate worldwide, and atherosclerosis (AS) is the main factor inducing cardiovascular disease, of which lipid deposition in the vessel wall is the main marker of AS. Currently, although statins can be used to lower lipids and low-density lipoprotein (LDL) in AS, the cure rate for AS remains low. Therefore, there is an urgent need to develop new therapeutic approaches, and stem cells are now widely studied, while stem cells are a class of cell types that always maintain the ability to differentiate and can differentiate to form other cells and tissues, and stem cell transplantation techniques have shown efficacy in the treatment of other diseases. With the establishment of cellular therapies and continued research in stem cell technology, stem cells are also being used to address the problem of AS. In this paper, we focus on recent research advances in stem cell therapy for AS and briefly summarize the relevant factors that induce the formation of AS. We mainly discuss the efficacy and application prospects of mesenchymal stem cells (MSCs) for the treatment of AS, in addition to the partial role and potential of exosomes in the treatment of AS. Further, provide new ideas for the clinical application of stem cells.
... There is also a continuous phenotype between them, and the subtype transition of macrophages plays a key role in the transition between the in ammatory and proliferative phases [39] . MSCs can mediate the polarization of macrophages in a variety of ways, and macrophages can respond to microenvironmental factors in tissues [40] . The results of this study con rmed that hPDLSCs exhibit immunomodulatory functions in vitro, and inhibit the polarization of M1 macrophages. ...
Background：Human periodontal ligament stem cells (hPDLSCs) have a superior ability to promote the formation of new bones, and achieve tissue regeneration. However, mesenchymal stem cells (MSCs) are placed in harsh environments after transplantation, and the hostile microenvironment reduces their stemness and hinders their therapeutic effects. Klotho is an antiaging protein that participates in the regulation of stress resistance. In our previous study, we demonstrated the protective ability of Klotho in hPDLSCs.
Methods：A cranial bone defect model of rats was constructed and the hPDLSCs with or without Klotho pretreatment were transplanted into the defects. Histochemical staining and micro-computed tomography were used to detect cell survival, osteogenesis, and immunoregulatory effects of hPDLSCs after transplantation. The in vitro capacity of hPDLSCs was measured by a macrophage polarization test and the inflammatory level of macrophages. Furthermore, we explored autophagy activity in hPDLSCs, which may be affected by Klotho to regulate cell homeostasis.
Results：Pretreatment with the recombinant human Klotho protein improved cell survival after hPDLSC transplantation, and enhanced their ability to promote bone regeneration. Furthermore, Klotho pretreatment can promote stem cell immunomodulatory effects in macrophages and modulate cell autophagy activity, in vivo and in vitro.
Conclusion: These findings suggest that Klotho protein enhances the immunomodulatory ability of hPDLSCs and protects stem cells from stress after transplantation to maintain stem cell function by inhibiting cell autophagy.
... Human umbilical cord mesenchymal stem cell-derived Exos ameliorate laser-induced retinal injury by down-regulation of VEGF-A in rats (140). Moreover, MSC-derived Exos regulate macrophage polarization and diminish VEGF secretion, two known triggering mechanisms of CNV in AMD; thus, they are able to regulate abnormal neovascularization (141,142). EVs' diagnostic and therapeutic applications in AMD are still in the early preclinical stages. Further investigations and trials are substantial to determine their safety, efficacy, and generalizability ( Table 2). ...
Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term “inflammatory eye diseases” refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles’ and exosomes’ pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.
... Surprisingly, EVs derived from BM-MSCs (BM-MSC-EVs) were reported to achieve "One Stone Two Birds". They decreased the infiltration number of M1j phenotype and promoted M2j phenotype polarization in the plaque of atherosclerosis through miR-let7/IGF2BP1/PTEN and miR-let7/HMGA2/NF-kB signaling pathways, simultaneously (26). ...
Various intractable inflammatory diseases caused by disorders of immune systems have pressed heavily on public health. Innate and adaptive immune cells as well as secreted cytokines and chemokines are commanders to mediate our immune systems. Therefore, restoring normal immunomodulatory responses of immune cells is crucial for the treatment of inflammatory diseases. Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are nano-sized double-membraned vesicles acting as paracrine effectors of MSCs. MSC-EVs, containing a variety of therapeutic agents, have shown great potential in immune modulation. Herein, we discuss the novel regulatory functions of MSC-EVs from different sources in the activities of innate and adaptive immune cells like macrophages, granulocytes, mast cells, natural killer (NK) cells, dendritic cells (DCs) and lymphocytes. Then, we summarize the latest clinical trials of MSC-EVs in inflammatory diseases. Furthermore, we prospect the research trend of MSC-EVs in the field of immune modulation. Despite the fact that the research on the role of MSC-EVs in regulating immune cells is in infancy, this cell-free therapy based on MSC-EVs still offers a promising solution for the treatment of inflammatory diseases.
... The EV contents, for example, miRNAs [44][45][46], cytokines such as monocyte chemoattractant protein-1 (MCP-1), and IL-10 [47,48], and proteins such as tumor necrosis factor-α-stimulated gene/protein-6 (TSG-6), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and STAT3 [49][50][51] in cell-derived EVs have been shown to be active stimulators mediating in monocyte polarization in EV-recipient cells. ...
Malaria is a life-threatening tropical arthropod-borne disease caused by Plasmodium spp. Monocytes are the primary immune cells to eliminate malaria-infected red blood cells. Thus, the monocyte’s functions are one of the crucial factors in controlling parasite growth. It is reasoned that the activation or modulation of monocyte function by parasite products might dictate the rate of disease progression. Extracellular vesicles (EVs), microvesicles, and exosomes, released from infected red blood cells, mediate intercellular communication and control the recipient cell function. This study aimed to investigate the physical characteristics of EVs derived from culture-adapted P. falciparum isolates (Pf-EVs) from different clinical malaria outcomes and their impact on monocyte polarization. The results showed that all P. falciparum strains released similar amounts of EVs with some variation in size characteristics. The effect of Pf-EV stimulation on M1/M2 monocyte polarization revealed a more pronounced effect on CD14+CD16+ intermediate monocytes than the CD14+CD16− classical monocytes with a marked induction of Pf-EVs from a severe malaria strain. However, no difference in the levels of microRNAs (miR), miR-451a, miR-486, and miR-92a among Pf-EVs derived from virulent and nonvirulent strains was found, suggesting that miR in Pf-EVs might not be a significant factor in driving M2-like monocyte polarization. Future studies on other biomolecules in Pf-EVs derived from the P. falciparum strain with high virulence that induce M2-like polarization are therefore recommended.
... As an example, administration of BM-MSCs-derived EVs into high-fat diet ApoE -/mice stimulated M2 polarization of residual macrophages, which led to the decrease in the inflammation and reduction of atherosclerotic plaque area. The mechanism of EV action was possibly related to the transfer of miR-let7 family that regulated activity of downstream signaling pathways, such as NF-kB and PTEN (130). Similar immunomodulatory effect was also shown for AT-MSC-EVs, that diminished inflammatory activation of both aortic endothelial cells stimulated with tumor necrosis factor alpha (TNF-a), as well as LPS-stimulated macrophages in vitro, reducing atherosclerotic plaque in vivo in low-density lipoprotein (LDL) receptor deficient (Ldlr -/-) mice fed with a high-fat diet (131). ...
In the last few decades, the practical use of stem cells (SCs) in the clinic has attracted significant attention in the regenerative medicine due to the ability of these cells to proliferate and differentiate into other cell types. However, recent findings have demonstrated that the therapeutic capacity of SCs may also be mediated by their ability to secrete biologically active factors, including extracellular vesicles (EVs). Such submicron circular membrane-enveloped vesicles may be released from the cell surface and harbour bioactive cargo in the form of proteins, lipids, mRNA, miRNA, and other regulatory factors. Notably, growing evidence has indicated that EVs may transfer their bioactive content into recipient cells and greatly modulate their functional fate. Thus, they have been recently envisioned as a new class of paracrine factors in cell-to-cell communication. Importantly, EVs may modulate the activity of immune system, playing an important role in the regulation of inflammation, exhibiting broad spectrum of the immunomodulatory activity that promotes the transition from pro-inflammatory to pro-regenerative environment in the site of tissue injury. Consequently, growing interest is placed on attempts to utilize EVs in clinical applications of inflammatory-related dysfunctions as potential next-generation therapeutic factors, alternative to cell-based approaches. In this review we will discuss the current knowledge on the biological properties of SC-derived EVs, with special focus on their role in the regulation of inflammatory response. We will also address recent findings on the immunomodulatory and pro-regenerative activity of EVs in several disease models, including in vitro and in vivo preclinical, as well as clinical studies. Finally, we will highlight the current perspectives and future challenges of emerging EV-based therapeutic strategies of inflammation-related diseases treatment.
... The dysregulation of the CD47-SIRPα axis may also contribute to the pathogenesis of atherosclerosis in humans [100]. Additionally, miR-let7 has been shown to attenuate the progression of atherosclerosis in ApoE −/− mice and facilitate M2 macrophage infiltration and polarization [101]. miR-205-5p is a regulator of macrophage lipid transport and contributes to atherosclerosis [102]. ...
Cardiovascular diseases (CVDs) are the leading cause of hospitalization and death worldwide , especially in developing countries. The increased prevalence rate and mortality due to CVDs, despite the development of several approaches for prevention and treatment, are alarming trends in global health. Chronic inflammation and macrophage infiltration are key regulators of the initiation and progression of CVDs. Recent data suggest that epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and RNA modifications, regulate cell development, DNA damage repair, apoptosis, immunity, calcium signaling, and aging in cardiomyocytes; and are involved in macrophage polarization and contribute significantly to cardiac disease development. Cardiac macrophages not only trigger damaging inflammatory responses during atherosclerotic plaque formation, myocardial injury, and heart failure but are also involved in tissue repair, re-modeling, and regeneration. In this review, we summarize the key epigenetic modifications that influence macrophage polarization and contribute to the pathophysiology of CVDs, and highlight their potential for the development of advanced epigenetic therapies.
... The adipose tissue-derived exosomes induce RAW264.7 macrophages to switch to the M1 phenotype, increase the secretion of proinflammatory cytokines (TNF-α, IL-6), and exacerbate atherosclerosis in hyperlipidemic ApoE -/mice [69]. In contrast, mesenchymal stem cell-derived exosomes can induce more M2type macrophage markers, reduce the infiltration of M1 macrophages and shrink the area of atherosclerotic plaques in ApoE -/mice [70]. A similar study finds that mesenchymal stem cellderived exosomes containing miR-21a-5p can promote macrophage polarization and reduce macrophage infiltration by targeting KLF6 and ERK1/2 signaling pathways, thereby attenuating the development of atherosclerosis [71]. ...
Atherosclerosis is a chronic inflammatory vascular disease and one of the leading causes of death worldwide. Macrophages play an important role in atherosclerosis in the inflammatory response, cell-cell communications, plaque growth, and plaque rupture in atherosclerotic lesions. Here we review the sources, functions, and complex phenotypes of macrophages in the progression of atherosclerotic, and discuss the recent approaches in modulating macrophage autophagy and phenotypic transformation for atherosclerosis treatment. We then focus on the drug delivery strategies that target macrophages or use macrophage membrane-coated particles to deliver therapeutics to the lesion sites. These biomaterial-based approaches to target, modulate, or engineer macrophages have broad applications for disease therapies and tissue regeneration.
... P<0.05; Figure 3C). Previous studies have shown that Mjs mainly comprise two distinct functional phenotypes: classically activated Mjs (M1) and alternatively activated Mjs (M2) (25). Our flow cytometry analysis revealed that M1-phenotype Mjs (CD16 + CD64 + CD163 -) were predominant ( Figure 3D). ...
Background
Within the past 3-5 years, Mycoplasma pneumoniae has become a major pathogen of community-acquired pneumonia in children. The pathogenic mechanisms involved in M. pneumoniae infection have not been fully elucidated.
Methods
Previous protein microarray studies have shown a differential expression of CXCL9 after M. pneumoniae infection. Here, we conducted a hospital-based study to explore the clinical significance of the type 1 immune response inflammatory factors interferon (IFN)-γ and CXCL9 in patients with M. pneumoniae pneumonia (MPP). Then, through in vitro experiments, we explored whether CARDS toxin stimulated F-DCs (dendritic cells incubated with Flt3L) to promote Th-cell differentiation; we also investigated the IFN-γ-induced CXCL9 secretion pathway in macrophages and the role of CXCL9 in promoting Th1 cell migration.
Results
The CXCL9 expression level was upregulated among patients with a higher fever peak, fever duration of greater than 7 days, an imaging manifestation of lobar or segmental, or combined pleural effusion (P<0.05). The peripheral blood levels of IFN-γ and CXCL9, which were higher in patients than in the healthy control group, were positively correlated with each other (r=0.502, P<0.05). In patients, the CXCL9 expression level was significantly higher in the bronchoalveolar lavage fluid (BALF) than in the peripheral blood, and the BALF CXCL9 expression level was higher than that in the healthy control group (all P<0.05). Our flow cytometry analysis revealed that M1-phenotype macrophages (CD16⁺ CD64⁺ CD163⁻) were predominant in the BALF from children with MPP. In in vitro experiments, F-DCs stimulated with CARDS toxin promoted the differentiation of CD4⁺ IFN-γ⁺ Th (Th1) cells (P<0.05). Moreover, IFN-γ induced high levels of CXCL9 expression in M1-type macrophages in a dose-dependent and time-dependent manner. Additionally, macrophages transfection with STAT1-siRNA-1 downregulated the expression of CXCL9 (P<0.05), and CXCL9 promoted Th1 cell migration (P<0.05).
Conclusions
Our findings suggest that CARDS toxin induces a type 1 immune response positive feedback loop during M. pneumoniae infection; this putative mechanism may be useful in future investigations of immune intervention approaches for M. pneumoniae pneumonia.
... EVs from different cell types, such as MSCs [126] or platelets [127], have shown promising effects on the treatment of atherosclerosis and plaque development. These EVs have been shown to influence the behavior of cells associated with atherosclerosis; for example, MSCs-derived EVs can reduce macrophage infiltration through miRNA delivery [128], with antiinflammatory effects on eosinophils and endothelial cells (ECs) [129,130]. In another study, the authors demonstrated that EVs and associated miRNAs from endothelial progenitor cells can target ECs in atherosclerotic plaques, reducing oxidative stress, inflammation, and endothelial contractile dysfunction [131]. ...
Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases.
... M2 macrophages play an anti-inflammatory role and secrete VEGF, IL-10, and TGF-β, which can eliminate inflammation and promote wound healing, tissue repair, and regeneration and angiogenesis [12,13]. Studies have found that MSC-derived exosomes can induce macrophage polarization into the M2 phenotype, improve cardiac injury following myocardial infarction, delay the formation of atherosclerotic plaques, and accelerate wound healing [14,15,16]. ...
Diabetic lower limb ischemia is an intractable disease that leads to amputation and even death. Recently, adipose-derived stem cell-secreted exosomes (ADSC-Exo) have been reported as a potential therapeutic approach, but its specific mechanism of action is unknown. Studies have found that exosomes derived from stem cells can reduce inflammation and promote tissue repair. Macrophages play an important role in the development and repair of inflammation in lower limb ischemic tissue, but the specific regulation of ADSC-Exo in macrophages has rarely been reported. The present study aimed to verify whether ADSC-Exo could promote angiogenesis by regulating macrophages to reduce the level of inflammation in diabetic ischemic lower limbs. In this study, adipose-derived stem cells (ADSCs) were obtained and identified, and ADSC-Exos were isolated using ultracentrifugation and characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blotting analysis. The uptake of ADSC-Exos by macrophages was observed using immunofluorescence, and macrophage polarization induced by ADSC-Exos was identified by flow cytometry, immunofluorescence and ELISA. The effects of ADSC-Exos on the proliferation, apoptosis, migration and adhesion of macrophages were evaluated using CCK-8 assay, flow cytometry, Transwell assay, scratch and adhesion experiments, and ELISA assay. The polarization-related JAK/STAT6 signaling pathway was explored by using western blotting. A lower limb ischemic model of type 2 diabetic mice was established and ADSC-Exos was intramuscularly injected into the mice. The blood flow in the lower limbs was assessed using a laser Doppler flowmeter, while the level of angiogenesis was determined using immunohistochemistry and immunofluorescence. The results of this study prove that ADSC-Exos induced M2-phenotype polarization of macrophages via the JAK/STAT6 signaling pathway can promote the proliferation, migration and adhesion of M2 macrophages, inhibit the apoptosis of macrophages, and promote the angiogenesis and revascularization of ischemic lower limbs in type 2 diabetic mice. Thus, this study provides a theoretical and experimental basis for the clinical treatment of diabetic lower limb ischemic disease.
... Some exosomal miRs such as miR-100-5p, miR-512-3p, let-7 family, and miR-21a-5p are derived from MSCs and have various properties. As these exosomal miRs can induce M2 macrophage polarization, they are capable of suppressing atherosclerosis [128,129]. Bone-marrow-derived macrophages (BMDMs) can release exosomal miRs with anti-inflammatory properties, including miR-99a, miR-146b, and miR-378a, which are capable of promoting M2 polarization in BMDMs [127,130]. Wu et al. generated exosomes with anti-inflammatory functions in atherosclerosis. ...
Macrophages are influential members of the innate immune system that can be reversibly polarized by different microenvironment signals. Cell polarization leads to a wide range of features, involving the migration, development, and organization of the cells. There is mounting evidence that macrophage polarization plays a key role in the initiation and development of a wide range of diseases. This study aims to give an overview of macrophage polarization, their different subtypes, and the importance of alternatively activated M2 macrophage and classically activated M1 macrophage in immune responses and pathological conditions. This review provides insight on the role of exosomes in M1/M2-like macrophage polarization and their potential as a promising therapeutic candidate.
The targeted drug delivery field is rapidly advancing, focusing on developing biocompatible nanoparticles that meet rigorous criteria of non‐toxicity, biocompatibility, and efficient release of encapsulated molecules. Conventional synthetic nanoparticles (SNPs) face complications such as elevated immune responses, complex synthesis methods, and toxicity, which restrict their utility in therapeutics and drug delivery. Extracellular vesicles (EVs) have emerged as promising substitutes for SNPs, leveraging their ability to cross biological barriers, biocompatibility, reduced toxicity, and natural origin. Notably, mesenchymal stem cell‐derived EVs (MSC‐EVs) have garnered much curiosity due to their potential in therapeutics and drug delivery. Studies suggest that MSC‐EVs, the central paracrine contributors of MSCs, replicate the therapeutic effects of MSCs. This review explores the characteristics of MSC‐EVs, emphasizing their potential in therapeutics and drug delivery for various diseases, including CRISPR/Cas9 delivery for gene editing. It also delves into the obstacles and challenges of MSC‐EVs in clinical applications and provides insights into strategies to overcome the limitations of biodistribution and target delivery.
Atherosclerosis (AS) is considered to be one of the major causes of cardiovascular disease. Its pathological microenvironment is characterised by increased production of reactive oxygen species, lipid oxides, and excessive inflammatory factors, which accumulate at the monolayer endothelial cells in the vascular wall to form AS plaques. Therefore, intervention in the pathological microenvironment would be beneficial in delaying AS. Researchers have designed biomimetic nanomedicines with excellent biocompatibility and the ability to avoid being cleared by the immune system through different therapeutic strategies to achieve better therapeutic effects for the characteristics of AS. Biomimetic nanomedicines can further enhance delivery efficiency and improve treatment efficacy due to their good biocompatibility and ability to evade clearance by the immune system. Biomimetic nanomedicines based on therapeutic strategies such as neutralising inflammatory factors, ROS scavengers, lipid clearance and integration of diagnosis and treatment are versatile approaches for effective treatment of AS. The review firstly summarises the targeting therapeutic strategy of biomimetic nanomedicine for AS in recent 5 years. Biomimetic nanomedicines using cell membranes, proteins, and extracellular vesicles as carriers have been developed for AS.
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post‐traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID‐19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration and poor targeting, traditional anti‐rheumatic drugs have unsatisfactory treatment efficacy and strong side effects, including myelosuppression, liver or kidney function damage, and malignant tumors. Consequently, mesenchymal stem cells (MSCs)‐involved therapy is proposed for RA therapy as a benefit of their immunosuppressive and tissue‐repairing effects. This review summarizes the progress of MSCs‐involved RA therapy through suppressing inflammation and promoting tissue regeneration and predicts their potential clinical application.
The development of numerous diseases is significantly influenced by inflammation. Macrophage-derived exosomes (M-Exos) play a role in controlling inflammatory reactions in various conditions, including chronic inflammatory pain, hypertension, and diabetes. However, the specific targets and roles of M-Exos in regulating inflammation in diseases remain largely unknown. This review summarizes current knowledge on M-Exos biogenesis and provides updated information on M-Exos’ biological function in inflammation modulation. Furthermore, this review highlights the functionalization and engineering strategies of M-Exos, while providing an overview of cutting-edge approaches to engineering M-Exos and advancements in their application as therapeutics for inflammation modulation. Finally, multiple engineering strategies and mechanisms are presented in this review along with their perspectives and challenges, and the potential contribution that M-Exos may have in diseases through the modulation of inflammation is discussed.
Introduction:
Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide.
Areas covered:
Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development.
Exert opinion:
As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.
Today, cardiovascular diseases are among the biggest public health threats worldwide. Atherosclerosis, a chronic inflammatory disease with complex aetiology and pathogenesis, predispose many of these conditions, including the high mortality rate-causing ischaemic heart disease and stroke. Nevertheless, despite the alarming prevalence and absolute death rate, established treatments for atherosclerosis are unsatisfactory in terms of efficacy, safety, and patient acceptance. The rapid advancement of technologies in healthcare research has paved new treatment approaches, namely cell-based and nanoparticle-based therapies, to overcome the limitations of conventional therapeutics. This paper examines the different facets of each approach, discusses their principles, strengths, and weaknesses, analyses the main targeted pathways and their contradictions, provides insights on current trends as well and highlights any unique mechanisms taken in recent years to combat the progression of atherosclerosis.
Macrophages play fundamental roles in atherosclerotic plaque formation, growth, and regression. These cells are extremely plastic and perform different immune functions depending on the stimuli they receive. Initial in vitro studies have identified specific metabolic pathways that are crucial for the proper function of pro-inflammatory and pro-resolving macrophages. However, the plaque microenvironment, especially in the context of insulin resistance and type 2 diabetes, constantly challenges macrophages with several simultaneous inflammatory and metabolic stimuli, which may explain why atherosclerosis is accelerated in diabetic patients. In this mini review, we discuss how macrophage mitochondrial function and metabolism of carbohydrates, lipids, and amino acids may be affected by this complex plaque microenvironment and how risk factors associated with type 2 diabetes alter the metabolic rewiring of macrophages and disease progression. We also briefly discuss current challenges in assessing macrophage metabolism and identify future tools and possible strategies to alter macrophage metabolism to improve treatment options for diabetes-associated atherosclerosis.
Myocardial infarction, which is the most important clinical sign of coronary artery disease, is one of the leading causes of global mortality, despite current treatment methods. Stem cell transplantation, which fastens on the regeneration of damaged tissue, has been suggested as an alternative approach in cardiac regenerative medicine; however, complications such as low survival in ischemic conditions, immune rejection, and teratoma formation have limited the routine use of stem cells in clinical treatments.
Exosomes, which have been shown to play an essential role in intracellular communication and carry protein, lipid, and nucleic acid-based rich cargo content, have emerged as a new potential in the diagnosis and treatment of many diseases such as neurodegenerative diseases, cancer, and cardiovascular diseases in recent years. First findings have brought into the open that the exosomes secreted by local cells in the myocardium layer and stem cells have an essential role in the repair of cardiac damage because they involve pro-angiogenic, pro-survival, anti-fibrotic, or anti-apoptotic molecules.
This review has comprehensively discussed the rich cargo content of somatic and stem cell-derived exosomes, their regulatory mechanisms in amelioration of the pathophysiology of coronary artery disease, molecular interactions of exosomal cargo contents, strengths, and limitations of exosomal strategies.
This study aims to elucidate the role of miR-129/miR-342 loaded in exosomes derived from vascular smooth muscle cells (VSMCs) stimulated by intermittent hypoxia in calcified aortic valvular disease (CAVD). Bioinformatics analysis was conducted to identify differentially expressed miRs in VSMCs-derived exosomes and CAVD samples, and their potential target genes were predicted. VSMCs were exposed to intermittent hypoxia to induce stimulation, followed by isolation of exosomes. Valvular interstitial cells (VICs) were cultured in vitro to investigate the impact of miR-129/miR-342 on VICs’ osteogenic differentiation and aortic valve calcification with eIF2α. A CAVD mouse model was established using ApoE knockout mice for in vivo validation. In CAVD samples, miR-129 and miR-342 were downregulated, while eIF2α and ATF4 were upregulated. miR-129 and miR-342 exhibited inhibitory effects on eIF2α through targeted regulation. Exosomes released from intermittently hypoxia-stimulated VSMCs contained miR-129 and miR-342. Overexpression of miR-129 and miR-342, or silencing ATF4, suppressed VICs’ osteogenic differentiation and aortic valve calcification, which could be rescued by overexpressed eIF2α. Collectively, intermittent hypoxia stimulation of VSMCs leads to the secretion of exosomes that activate the miR-129/miR-342 dual pathway, thereby inhibiting the eIF2α/ATF4 axis and attenuating VICs’ osteogenic differentiation and CAVD progression.
Atherosclerosis (AS) is the leading cause of cardiovascular disease, causing a major burden on patients as well as families and society. Exosomes generally refer to various lipid bilayer microvesicles originating from different cells that deliver various bioactive molecules to the recipient cells, exerting biological effects in cellular communication and thereby changing the internal environment of the body. The mechanisms of correlation between exosomes and the disease process of atherosclerosis have been recently clarified. Exosomes are rich in nucleic acid molecules and proteins. For example, the exosome miRNAs reportedly play important roles in the progression of atherosclerotic diseases. In this review, we focus on the composition of exosomes, the mechanism of their biogenesis and release, and the commonly used methods for exosome extraction. By summarizing the latest research progress on exosomes and atherosclerosis, we can explore the advances in the roles of exosomes in atherosclerosis to provide new ideas and targets for atherosclerosis prevention, diagnosis, and treatment.
Atherosclerosis, formed by fibrofatty lesions in the artery wall, underpins myocardial infarctions, strokes and disabling peripheral artery diseases. Inflammation with multiple maladaptive roles runs through atherosclerotic inception, propagation, and complications. Given degree of inflammation differing among atherosclerotics, inflammation-targeted nanomedicine may produce individualized monitoring and manipulation of inflammatory regulators beyond traditionally slowing down atherosclerosis progression. Equipped with biomimetic membrane, microenvironment-responsive and targeting structures, nanomedicines could escape from the innate immune system and autonomously navigate to targeted lesions, thereby muting inflammation in atherosclerotic sites. Moreover, nanoparticles’ advantages go beyond advancing pharmacology. The optimal physicochemical properties of nanoparticles favor noninvasive imaging function to provide diagnostic and prognostic information of atherosclerotic plaques. Despite efficacious ability of the preclinical anti-inflammation nanotherapeutics to reduce atherosclerotic risks, future translation of inflammation-targeted nanomedicines requires to comprehensively refine the strategies that the nanomedicines forestall inflammatory pathways via systemic exposure, drug-cell interactions, and endothelial barrier reconstruction. In this review, we outline the development of diverse nanomedicines to specifically identify pathophysiological changes and combat advanced atherosclerosis along with dynamically tracing inflammatory markers. Finally, challenges and opportunities of inflammation-targeted nanomedicines are highlighted to pave avenues toward personalized medicine for atherosclerosis to stem the growing global burden of cardiovascular diseases.
Efferocytosis, responsible for apoptotic cell clearance, is an essential factor against atherosclerosis. It is reported that efferocytosis is severely impaired in fibroatheroma, especially in vulnerable thin cap fibroatheroma. However, there is a shortage of studies on efferocytosis defects in cell and animal models. Here, the impacts of oxidized low density lipoprotein (ox‐LDL) and glut 1 inhibitor (STF31) on efferocytosis of macrophages are studied, and an evaluation system is constructed. Through regulating the cell ratios and stimulus, three types of atherosclerotic spheroids are fabricated, and a necrotic core emerges with surrounding apoptotic cells. Rat models present a similar phenomenon in that substantial apoptotic cells are uncleared in time in vulnerable plaque, and the model period is shortened to 7 weeks. Mechanism studies reveal that ox‐LDL, through mRNA and miRNA modulation, downregulates efferocytosis receptor (PPARγ/LXRα/MerTK), internalization molecule (SLC29a1), and upregulates the competitive receptor CD300a that inhibits efferocytosis receptor‐ligand binding process. The foam cell differentiation has also confirmed that CD36 and Lp‐PLA2 levels are significantly elevated, and macrophages present an interesting transition into prothrombic phenotype. Collectively, the atherosclerotic models featured by efferocytosis defect provide a comprehensive platform to evaluate the efficacy of medicine and biomaterials for atherosclerosis treatment.
Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases. Since alterations in cell–cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell–cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV’s content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.
Tissue engineering offers novel solutions to overcome the limitations of currently used heart valve substitutes and small vessel bypass grafts. The main benefit of tissue-engineered substitutes is their intrinsic potential to grow and remodel in response to changing environmental conditions, which is particularly important for cardiovascular tissues, such as blood vessels and heart valves. The traditional tissue engineering triad of cells, scaffolds and stimuli to culture living replacement tissues in the lab has been nuanced with more recent strategies of pure cell-based or pure scaffold-based tissue engineering scaffolds, and the role of patient-specific microenvironmental stimuli (hemodynamic, immunological) is gaining attention as the focus shifts from creating the perfect tissue in the lab to creating adequate integration of tissue-engineered grafts in the body.
Considerable progress has been made in recent years with the development of tissue engineered heart valves and blood vessels. As these laboratory-based projects make translational steps towards the clinic, a new set of hurdles need to be negotiated. These include the choice between, in vitro, in vivo and in situ strategies, immunogenicity of implanted material, tissue growth and adaptation and use of percutaneous implantation of tissue engineered constructs. In addition, bioengineered tissues may serve as in vitro platforms to model vascular and valvular diseases, investigate underlying pathomechanisms and develop more efficient and/or novel therapeutic strategies. In this research topic, we aim to address several of the current scientific and translational questions: what inspiration can we draw from native valvular and vascular development? How is the integration of a tissue engineered graft influenced by patient-specific conditions, such as immunological or hemodynamic conditions? Can we use tissue-engineered (disease) models to predict this?
Osteoarthritis (OA) is a low-grade inflammatory disorder of the joints that causes deterioration of the cartilage, bone remodeling, formation of osteophytes, meniscal damage, and synovial inflammation (synovitis). The synovium is the primary site of inflammation in OA and is frequently characterized by hyperplasia of the synovial lining and infiltration of inflammatory cells, primarily macrophages. Macrophages play a crucial role in the early inflammatory response through the production of several inflammatory cytokines, chemokines, growth factors, and proteinases. These pro-inflammatory mediators are activators of numerous signaling pathways that trigger other cytokines to further recruit more macrophages to the joint, ultimately leading to pain and disease progression. Very few therapeutic alternatives are available for treating inflammation in OA due to the condition’s low self-healing capacity and the lack of clear diagnostic biomarkers. In this review, we opted to explore the immunomodulatory properties of mesenchymal stem cells (MSCs) and their paracrine mediators-dependent as a therapeutic intervention for OA, with a primary focus on the practicality of polarizing macrophages as suppression of M1 macrophages and enhancement of M2 macrophages can significantly reduce OA symptoms.
Backgound:
The inability to detect premature atherosclerosis significantly hinders implementation of personalized therapy to prevent coronary heart disease. A comprehensive understanding of arterial protein networks and how they change in early atherosclerosis could identify new biomarkers for disease detection and improved therapeutic targets.
Methods:
Here we describe the human arterial proteome and proteomic features strongly associated with early atherosclerosis based on mass spectrometry analysis of coronary artery and aortic specimens from 100 autopsied young adults (200 arterial specimens). Convex analysis of mixtures, differential dependent network modeling, and bioinformatic analyses defined the composition, network rewiring, and likely regulatory features of the protein networks associated with early atherosclerosis and how they vary across 2 anatomic distributions.
Results:
The data document significant differences in mitochondrial protein abundance between coronary and aortic samples (coronary>aortic), and between atherosclerotic and normal tissues (atherosclerotic<normal), and major alterations in tumor necrosis factor, insulin receptor, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-γ protein networks, as well, in the setting of early disease. In addition, a subset of tissue protein biomarkers indicative of early atherosclerosis was shown to predict anatomically defined coronary atherosclerosis when measured in plasma samples in a separate clinical cohort (area under the curve=0.92 [0.83-0.96]), thereby validating the use of human tissue proteomics to discover relevant plasma biomarkers for clinical applications. In addition to the specific proteins and pathways identified here, the publicly available data resource and the analysis pipeline used illustrate a strategy for interrogating and interpreting the proteomic architecture of tissues that may be relevant for other chronic diseases characterized by multicellular tissue phenotypes.
Conclusions:
The human arterial proteome can be viewed as a complex network whose architectural features vary considerably as a function of anatomic location and the presence or absence of atherosclerosis. The data suggest important reductions in mitochondrial protein abundance in early atherosclerosis and also identify a subset of plasma proteins that are highly predictive of angiographically defined coronary disease.
Atherosclerosis is the major cause of cardiovascular diseases. Current evidences indicate that inflammation is involved in the pathogenesis of atherosclerosis. Human gingiva-derived mesenchymal stem cells (GMSC) have shown anti-inflammatory and immunomodulatory effects on autoimmune and inflammatory diseases. However, the function of GMSC in controlling atherosclerosis is far from clear. The present study is aimed to elucidate the role of GMSC in atherosclerosis, examining the inhibition of GMSC on macrophage foam cell formation, and further determining whether GMSC could affect the polarization and activation of macrophages under different conditions. The results show that infusion of GMSC to AopE−/− mice significantly reduced the frequency of inflammatory monocytes/macrophages and decreased the plaque size and lipid deposition. Additionally, GMSC treatment markedly inhibited macrophage foam cell formation and reduced inflammatory macrophage activation, converting inflammatory macrophages to anti-inflammatory macrophages in vitro. Thus, our study has revealed a significant role of GMSC on modulating inflammatory monocytes/macrophages and alleviating atherosclerosis.
In late 2016, the International Society for Extracellular Vesicles (ISEV) canvassed its members on standardization efforts in extracellular vesicle research. ISEV scientists responded with their views on the experimental guidelines and "minimal information for studies of EVs", or MISEV, published in 2014, and made recommendations for future adjustments and additions to these requirements. Here, we analyse these responses and provide a roadmap for ongoing ISEV efforts to promote rigor and reproducibility in EV science.
Mammalian cells can release different types of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies. Accumulating evidence suggests that EVs play a role in cell-to-cell communication within the tumor microenvironment. EVs' components, such as proteins, non-coding RNAs [microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)], messenger RNAs (mRNAs), DNA, and lipids, can mediate paracrine signaling in the tumor microenvironment. Recently, miRNAs encapsulated in secreted EVs have been identified in the extracellular space. Mature miRNAs that participate in intercellular communication are released from most cells, often within EVs, and disseminate through the extracellular fluid to reach remote target cells, including tumor cells, whose phenotypes they can influence by regulating mRNA and protein expression either as tumor suppressors or as oncogenes, depending on their targets. In this review, we discuss the roles of miRNAs on intercellular communication, the biological function of extracellular miRNAs, and their potential applications for diagnosis and therapeutics. We will give examples of miRNAs that behave as hormones.
Earlier research primarily attributed the effects of mesenchymal stem cell (MSC) therapies to their capacity for local engrafting and differentiating intomultiple tissue types.However, recent studies have revealed that implanted cells do not survive for long, and that the benefits of MSC therapy could be due to the vast array of bioactive factors they produce, which play an important role in the regulation of key biologic processes. Secretome derivatives, such as conditioned media or exosomes, may present considerable advantages over cells for manufacturing, storage, handling, product shelf life and their potential as a ready-to-go biologic product. Nevertheless, regulatory requirements for manufacturing and quality control will be necessary to establish the safety and efficacy profile of these products. Among MSCs, human uterine cervical stem cells (hUCESCs) may be a good candidate for obtaining secretome-derived products. hUCESCs are obtained by Pap cervical smear, which is a less invasive and painful method than those used for obtaining other MSCs (for example, from bone marrow or adipose tissue). Moreover, due to easy isolation and a high proliferative rate, it is possible to obtain large amounts of hUCESCs or secretome-derived products for research and clinical use.
Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.
Background:
Atherosclerosis is the leading cause of death and morbidity throughout industrialized nations, accounting for one-fifth of all deaths globally. Exosomes are bi-lipid membranous vesicles containing protein, lipid and nucleic acid contents that are released from cells via the endolysosomal pathway. Exosomes are derived from several cells including macrophages, dendritic cells, platelets as well as human serum.
Methods:
In this review, an overview of recent advances and the evidence for the role exosomes and exosome-derived microRNAs (miRNAs) in atherosclerosis are provided.
Results:
Recent evidence has shown that exosome derived from the cells mentioned above are involved in atherosclerosis, whose secretion appears to be regulated by various natural and experimental stimuli, physiological and pathological processes.
Conclusion:
Exosomes are now accepted as specifically secreted vesicles that enable intercellular communication and have become an exponentially growing interest to use them as possible relevant biomarkers in disease development such as cadiovascular disease, particular in atherosclerosis in addition to their minimally invasive clinical diagnosis.
Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called " exosomal shuttle RNA " (esRNA). Exosomes are small (50–90 nm) membrane vesicles of endocytic origin that are released into the extracellular environment on fusion of multivesicular bodies (MVB) with the plasma membrane 1. Many cells have the capacity to release exosomes, including reticulo-cytes 2 , dendritic cells 3 , B cells 4 , T cells 5 , mast cells 6 , epithelial cells 7 and tumour cells 8. The functions of exosomes are not completely understood, although it has been shown that exosomes can participate in the signalling events contributing to antigen presentation to T cells 4 and the development of tolerance 9. Several mechanisms have been hypothesized describing the interactions of exosomes and recipient cells. Exosomes can bind to cells through recep-tor–ligand interactions, similar to cell–cell communication mediating , for example, antigen presentation 4. Alternatively, exosomes could putatively attach or fuse with the target-cell membrane, delivering exosomal surface proteins and perhaps cytoplasm to the recipient cell 10,11. Finally, exosomes may also be internalized by the recipient cells by mechanisms such as endocytosis 12. Exosomes were isolated from a mast-cell line (MC/9), primary bone marrow-derived mast cells (BMMC) and a human mast-cell line (HMC-1) through a series of microfiltration and ultracentrifugation steps modified from what has been previously described 4. To confirm that the structures studied indeed are exosomes, they were examined by electron microscopy (Fig. 1a), flow cytometric analysis (FACS; Fig. 1b), and proteomic analysis (see Supplementary Information, Table S1). The electron micrographs of the exosomes revealed rounded structures with a size of approximately 50–80 nm, similar to previously described exo-somes 4,13–15. The identity of the studied vesicles was further confirmed as exosomes by FACS analysis (Fig. 1b), which show the presence of the surface protein CD63 — a commonly used marker of exosomes. Finally, extensive protein analysis of the MC/9 exosomes was performed on multiple samples using LC-MS/MS technology. A total of 271 proteins were identified (see Supplementary Information, Table S1) from three preparations of the isolated vesicles, of which 47 proteins were present in all three samples. More importantly, a large number of the proteins found in the preparations were the same as proteins previously identified in exosomes produced by other cells (that is, exosomes derived from intestinal epithelial cells, urine, dendritic cells, microglia, melanoma, T-cells and B-cells). In particular, 60% of the 47 proteins found in all samples of mast-cell exosomes have been previously found in other types of exosomes. Moreover, 39% of the 271 total proteins found in the analysed exosome samples have also been previously found in other types of exosomes. Thus, the electron microscopy, the FACS, and the detailed protein analyses each provided significant evidence in favour of the identification of the isolated vesicles as exosomes. The presence of nucleic acids was examined in exosomes derived from MC/9, BMMC and HMC-1 cells to define a potential mechanism by which exosomes may mediate cell–cell communication. These assessments showed that isolated exosomes contain no DNA (see Supplementary Information, Fig. S1). However, substantial amounts of RNA were detected by agarose gel electrophoresis, spectrophotometry
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe â '/â ' mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1 â '/â ' Apoe â '/â ' mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-Atherogenic cytokine production and foam cell formation.
Objective: Clinical and animal studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapies in cartilage repair. As the efficacy of many MSC-based therapies has been attributed to paracrine secretion, particularly extracellular vesicles/exosomes, we determine here if weekly intra-articular injections of human embryonic MSC-derived exosomes would repair and regenerate osteochondral defects in a rat model.
Methods: In this study, osteochondral defects were created on the trochlear grooves of both distal femurs in 12 adult rats. In each animal, one defect was treated with 100 μg exosomes and the contralateral defect treated with phosphate buffered saline (PBS). Intra-articular injections of exosomes or PBS were administered after surgery and thereafter weekly for a period of 12 weeks. Three unoperated age-matched animals served as native controls. Analyses were performed by histology, immunohistochemistry, and scoring at 6 and 12 weeks after surgery.
Results: Generally, exosome-treated defects showed enhanced gross appearance and improved histological scores than the contralateral PBS-treated defects. By 12 weeks, exosome-treated defects displayed complete restoration of cartilage and subchondral bone with characteristic features including a hyaline cartilage with good surface regularity, complete bonding to adjacent cartilage, and extracellular matrix deposition that closely resemble that of age-matched unoperated control. In contrast, there were only fibrous repair tissues found in the contralateral PBS-treated defects.
Conclusion: This study demonstrates for the first time the efficacy of human embryonic MSC exosomes in cartilage repair, and the utility of MSC exosomes as a ready-to-use and ‘cell-free’ therapeutic alternative to cell-based MSC therapy.
Stroke is the most common neurological cause of morbidity and mortality in industrialized countries, afflicting 15 million people every year. The numbers are expected to increase, mostly due to aging populations. One in five stroke patients dies, and one in three are left with permanent disabilities. Although some acute phase therapies such as intravenous recombinant tissue plasminogen activator (rt-PA) andendovascular treatment have been shown to improve ischemic stroke outcome, these therapies are available only for a small proportion of patients. The use of stem cells to replace brain cells lost during stroke is a long-term goal, and one which is difficult to achieve given that transplanted cells must integrate and restore neural pathways to regain function of damaged parts of the brain. Over the past decade the use of mesenchymal stromal cells (MSCs) as therapy has emerged as a particularly attractive option. MSCs are a class of multipotent, self-renewing cells that give rise to differentiated progeny when implanted into appropriate tissues. Herein, we present a review of the application of MSCs in ischemic stroke, including the source of MSCs, the route and timing of their delivery into the brain and the endpoints measured. Experimental data of transplantation of MSCs in animal stroke models suggest an improved functional recovery. The transplantation of MSCs influences a wide range of events by modulating the inflammatory environment, stimulating endogenous neurogenesis and angiogenesis and reducing the formation of glial scar, although the precise, underlying mechanism of this phenomenon remains unknown. The results from early clinical trials highlight the need to optimize variables such as cell selection and route of administration in order to translate these results into safe and successful clinical applications.
Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.
Aside from the well-established self-renewal and multipotent differentiation properties, mesenchymal stem cells exhibit both immunomodulatory and anti-inflammatory roles in several experimental autoimmune and inflammatory diseases. In this study, we isolated a new population of stem cells from human gingiva, a tissue source easily accessible from the oral cavity, namely, gingiva-derived mesenchymal stem cells (GMSCs), which exhibited clonogenicity, self-renewal, and multipotent differentiation capacities. Most importantly, GMSCs were capable of immunomodulatory functions, specifically suppressed peripheral blood lymphocyte proliferation, induced expression of a wide panel of immunosuppressive factors including IL-10, IDO, inducible NO synthase (iNOS), and cyclooxygenase 2 (COX-2) in response to the inflammatory cytokine, IFN-gamma. Cell-based therapy using systemic infusion of GMSCs in experimental colitis significantly ameliorated both clinical and histopathological severity of the colonic inflammation, restored the injured gastrointestinal mucosal tissues, reversed diarrhea and weight loss, and suppressed the overall disease activity in mice. The therapeutic effect of GMSCs was mediated, in part, by the suppression of inflammatory infiltrates and inflammatory cytokines/mediators and the increased infiltration of regulatory T cells and the expression of anti-inflammatory cytokine IL-10 at the colonic sites. Taken together, GMSCs can function as an immunomodulatory and anti-inflammatory component of the immune system in vivo and is a promising cell source for cell-based treatment in experimental inflammatory diseases.
Rudolph Virchow (1821-1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.
After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.
MicroRNAs (miRNAs) are a class of non-coding small RNAs that regulate the expression of target genes. They derive from pre-miRNAs that are enzymatically processed by dicer to ∼22 nucleotide mature miRNAs. Members of the pre-miRNA lethal-7 (let-7) are known to regulate cell proliferation and apoptosis. Here, we showed that the level of let-7c-5p, a key member of the let-7 family, was rapidly reduced in the traumatically injured foci in brains of adult C57BL/6J mice and gradually recovered to the pre-injury level 14 days after traumatic brain injury (TBI) induction. This finding led us to test whether upregulating let-7c-5p in murine cerebral tissue by intracerebroventricular injection (ICV) of let-7c-5p mimic could improve the outcomes of mice subjected to controlled cortical impact (CCI). We found that let-7c-5p overexpression attenuated TBI-induced neurological dysfunction and brain edema. The improvements were attributed to let-7c-5p-mediated inhibiting neuroinflammation and attenuation of microglia/macrophage activation, both inhibiting M1 polarization and enhancing M2 polarization. In vitro experiments, we observed that let-7c-5p was decreased in primary microglia activated by LPS treatment or oxygen/glucose deprivation (OGD). Transfection of let-7c-5p mimic suppressed the release of inflammatory mediators in cultured activated primary microglia. In addition, the expressions of caspase-3, a let-7c-5p putative target gene, and the PKC-δ which mediates effect of caspase-3 were inhibited by let-7c-5p in a murine model of TBI. Taken together, these results define the biological activities of cerebral let-7c-5p and delineate its therapeutic potential for improving the neurological outcome of TBI.
Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.
Atherosclerosis is a chronic inflammatory disease arising from an imbalance in lipid levels and the accumulation of cholesterol-laden macrophages in the artery wall. Crocin is an active ingredient of Crocus sativus L. This study established a rat coronary atherosclerosis model induced by vitamin D3 (VD3), to explore the effect of Crocin on lipid metabolism, macrophage polarization and the activity of inflammatory proteins. The results revealed that Crocin decreased blood lipid levels by decreasing the levels of endothelin (ET), total cholesterol (TC), triglyceridelow (TG) and low-density lipoprotein cholesterol (LDL-c), elevating the level of high-density lipoprotein cholesterin (HDL-c). Crocin also inhibited lipogenesis by suppressing the expression of lipogenesis-related proteins and elevating lipid catabolism-related proteins. Moreover, Crocin effectively alleviated inflammation by suppressing the expression of pro-inflammatory cytokines and increasing levels of anti-inflammatory cytokines. We further found that Crocin promoted macrophage polarization to the M2 phenotype by reducing M1 markers (CD40+ and CD11c+) and elevating M2 markers (CD68+ and CD206+). Finally, Crocin strongly inhibited the expression of NF-κB p65 and its translocation into the nucleus. Crocin partially counteracted nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 expression and the nuclei accumulation caused by NF-κB p65 overexpression. Taken together, our research indicated that Crocin inhibited lipogenesis and alleviated the inflammation in a VD3-induced rat coronary atherosclerosis model by promoting M2 macrophage polarization and maybe by inhibiting NF-κB p65 nuclear translocation. This study implicates Crocin as a potential therapeutic strategy for coronary atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of the arterial intima, occurring usually in the aged populations who are suffering from hypertension, dyslipidemia and diabetes for a long time. Research on atherosclerosis has shown that macrophage foam cell formation, inflammation, dyslipidemia and immune cells infiltration are all involved in regulating the onset and progression of atherosclerosis. Mesenchymal stem cells (MSCs) originated from different kinds of tissue are a group of cells possessing well-established self-renewal and multipotent differentiation properties as well as immunomodulatory and anti-inflammatory roles. Recent studies have displayed their dyslipidemia regulation functions. Transplantation of MSCs to atherosclerotic patients might be a new multifactorial therapeutic strategy to improve atherosclerosis. This review updates the advancement on MSCs and atherosclerosis.
Cancer cells grow in an environment comprised of multiple components that support tumor growth and contribute to therapy resistance. Major cell types in the tumor microenvironment are fibroblasts, endothelial cells and infiltrating immune cells all of which communicate with cancer cells. One way that these cell types promote cancer progression is by altering the expression of microRNAs (miRNAs), small noncoding RNAs that negatively regulate protein expression, either in the cancer cells or in the associated normal cells. Changes in miRNA expression can be brought about by direct interaction between the stromal cells and cancer cells, by paracrine factors secreted by any of the cell types or even through direct communication between cells through secreted miRNAs. Understanding the role of miRNAs in the complex interactions between the tumor and cells in its microenvironment is necessary if we are to understand tumor progression and devise new treatments.Oncogene advance online publication, 13 April 2015; doi:10.1038/onc.2015.89.
Transplantation of mesenchymal stem cells (MSCs) is beneficial in myocardial infarction and hind limb ischemia, but its ability to ameliorate atherosclerosis remains unknown. Here, the effects of MSCs on inhibiting endothelial dysfunction and atherosclerosis were investigated in human/mouse endothelial cells treated with oxidized low-density lipoprotein (oxLDL) and in apolipoprotein E-deficient (apoE(-/-)) mice fed a high-fat diet. Treatment with oxLDL inactivated the Akt/endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells. Coculture with human MSCs reversed the effects of oxLDL on endothelial cells and restored Akt/eNOS activity, eNOS level, and NO production. Reduction of endothelium-dependent relaxation and subsequent plaque formation were developed in apoE(-/-) mice fed a high-fat diet. Systemic infusion with mouse MSCs ameliorated endothelial dysfunction and plaque formation in high-fat diet-fed apoE(-/-) mice. Interestingly, treatment with interleukin-8 (IL8)/macrophage inflammatory protein-2 (MIP-2) alone induced the similar effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Neutralization antibodies (Abs) against IL8/MIP-2 also blocked the effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Consistently, MIP-2 injection alone induced the similar effect of MSCs on the endothelial function in high-fat diet-fed apoE(-/-) mice. The improvement in endothelial dysfunction by mouse MSCs was also blocked when pretreating MSCs with anti-MIP-2 Abs. In conclusion, MSC transplantation improved endothelial function and plaque formation in high-fat diet-fed apoE(-/-) mice. Activation of the Akt/eNOS pathway in endothelium by IL8/MIP-2 is involved in the protective effect of MSCs. The study helps support the use and clarify the mechanism of MSCs for ameliorating atherosclerosis.
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Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. In atherosclerotic lesions, macrophages respond to various environmental stimuli, such as modified lipids, cytokines, and senescent erythrocytes, which can modify their functional phenotypes. The results of studies on human atherosclerotic plaques demonstrate that the relative proportions of macrophage subsets within a plaque might be a better indicator of plaque phenotype and stability than the total number of macrophages. Understanding the function of specific macrophage subsets and their contribution to the composition and growth of atherosclerotic plaques would aid the identification of novel strategies to delay or halt the development of the disease and its associated pathophysiological consequences. However, most studies aimed at characterizing the phenotypes of human macrophages are performed in vitro and, therefore, their functional relevance to human pathology remains uncertain. In this Review, the diverse range of macrophage phenotypes in atherosclerotic lesions and their potential roles in both plaque progression and stability are discussed, with an emphasis on human pathology.
Mesenchymal stem cells (MSCs), whose mechanism of action is predominantly paracrine, are being widely tested for the treatment of a variety of human diseases. No one factor has been proven sufficient to mediate the therapeutic effects of MSCs. However, exosomes-membrane vesicles secreted by many cells, including MSCs-are appealing candidates as vectors of their efficacy. Exosomes can transport and deliver a large cargo of proteins, lipids, and nucleic acids and can modify cell and organ function. In addition to their key role as vehicles of intercellular communication, exosomes are increasingly recognized as biomarkers and prognosticators of disease. Moreover, they have the potential to be used as vehicles of gene and drug delivery for clinical application. This article reviews the biogenesis of exosomes, their molecular composition, and their role as messengers of intercellular communication, focusing on their potential as therapeutic vectors for stem cell therapy. Expected final online publication date for the Annual Review of Physiology Volume 77 is February 10, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.
In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrine-acting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.
Myocardial infarction is a leading cause of death among all cardiovascular diseases. The analysis of molecular mechanisms by which the ischemic myocardium initiates repair and remodeling indicates that secreted soluble factors are key players in communication to local and distant tissues, such as bone marrow. Recently, actively secreted membrane vesicles, including exosomes, are being recognized as new candidates with important roles in intercellular and tissue-level communication. In this review, we critically examine the emerging role of exosomes in local and distant microcommunication mechanisms after myocardial infarction. A comprehensive understanding of the role of exosomes in cardiac repair after myocardial infarction could bridge a major gap in knowledge of the repair mechanism after myocardial injury.
Osteoarthritis (OA), a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden that increases greatly as populations age. Yet no approved pharmacological intervention, biologic therapy or procedure prevents the progressive destruction of the OA joint. Mesenchymal stem cells (MSCs)-multipotent precursors of connective tissue cells that can be isolated from many adult tissues, including those of the diarthrodial joint-have emerged as a potential therapy. Endogenous MSCs contribute to maintenance of healthy tissues by acting as reservoirs of repair cells or as immunomodulatory sentinels to reduce inflammation. The onset of degenerative changes in the joint is associated with aberrant activity or depletion of these cell reservoirs, leading to loss of chondrogenic potential and preponderance of a fibrogenic phenotype. Local delivery of ex vivo cultures of MSCs has produced promising outcomes in preclinical models of joint disease. Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus, paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation. Several early-stage clinical trials, initiated or underway in 2013, are testing the delivery of MSCs as an intra-articular injection into the knee, but optimal dose and vehicle are yet to be established.
We have previously identified exosomes as the paracrine factor secreted by mesenchymal stem cells. Recently, we found that the key features of reperfusion injury, namely loss of ATP/NADH, increased oxidative stress and cell death were underpinned by proteomic deficiencies in ischemic/reperfused myocardium, and could be ameliorated by proteins in exosomes. To test this hypothesis in vivo, mice (C57Bl6/J) underwent 30min ischemia, followed by reperfusion (I/R injury). Purified exosomes or saline was administered 5min before reperfusion. Exosomes reduced infarct size by 45% compared to saline treatment. Langendorff experiments revealed that intact but not lysed exosomes enhanced viability of the ischemic/reperfused myocardium. Exosome treated animals exhibited significant preservation of left ventricular geometry and contractile performance during 28days follow-up. Within an hour after reperfusion, exosome treatment increased levels of ATP and NADH, decreased oxidative stress, increased phosphorylated-Akt and phosphorylated-GSK-3β, and reduced phosphorylated-c-JNK in ischemic/reperfused hearts. Subsequently, both local and systemic inflammation were significantly reduced 24h after reperfusion. In conclusion, our study shows that intact exosomes restore bioenergetics, reduce oxidative stress and activate pro-survival signaling, thereby enhancing cardiac function and geometry after myocardial I/R injury. Hence, mesenchymal stem cell-derived exosomes are a potential adjuvant to reperfusion therapy for myocardial infarction.
Objective:
Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis. The purpose of this study was to explore the presence and spatial distribution of polarized macrophage populations in human atherosclerosis.
Methods & results:
We used transcriptomics and immunohistochemistry to analyze macrophage subset dynamics in successive stages of atherogenesis. Developing lesions progressively accumulated both M1 and M2 cells, as was signified by the enhanced expression of associated markers at the transcriptional and protein level. Histologically, these markers were confined to overlapping, but spatially distinct CD68(+) areas of the intima. We subsequently quantified the presence of these markers in relation to morphological determinants of plaque stability. In line with their pro-inflammatory characteristics, M1 macrophages dominated the rupture-prone shoulder regions of the plaque over M2 polarized cells, while the fibrous caps of lesions showed no significant differences between subsets. In contrast, vascular adventitial tissue displayed a pronounced M2 activation profile. As expected, areas of intraplaque hemorrhage clearly associated with CD163 staining. Rather than being limited to complicated lesions, this M2 marker was also readily detectable in stable plaques. Finally, foamy macrophages displayed an ambiguous repertoire that incorporates individual M1 and M2 markers.
Conclusion:
M1 and M2 macrophage populations are present throughout atherogenesis. These subsets display disparity when it comes to their prevalence in morphological compartments of the vessel wall. Our current findings warrant continued investigation into the functional implications of polarized macrophage populations in human atherosclerosis.
The broad repertoire of secreted trophic and immunomodulatory cytokines produced by mesenchymal stem cells (MSCs), generally referred to as the MSC secretome, has considerable potential for the treatment of cardiovascular disease. However, harnessing this MSC secretome for meaningful therapeutic outcomes is challenging due to the limited control of cytokine production following their transplantation. This review outlines the current understanding of the MSC secretome as a therapeutic for treatment of ischemic heart disease. We discuss ongoing investigative directions aimed at improving cellular activity and characterizing the secretome and its regulation in greater detail. Finally, we provide insights on and perspectives for future development of the MSC secretome as a therapeutic tool.
Recent studies suggest that the therapeutic effects of stem cell transplantation following myocardial infarction (MI) are mediated by paracrine factors. One of the main goals in the treatment of ischemic heart disease is to stimulate vascular repair mechanisms. Here, we sought to explore the therapeutic angiogenic potential of mesenchymal stem cell (MSC) secretions. Human MSC secretions were collected as conditioned medium (MSC-CM) using a clinically compliant protocol. Based on proteomic and pathway analysis of MSC-CM, an in vitro assay of HUVEC spheroids was performed identifying the angiogenic properties of MSC-CM. Subsequently, pigs were subjected to surgical left circumflex coronary artery ligation and randomized to intravenous MSC-CM treatment or non-CM (NCM) treatment for 7 days. Three weeks after MI, myocardial capillary density was higher in pigs treated with MSC-CM (645 ± 114 vs 981 ± 55 capillaries/mm(2); P = 0.021), which was accompanied by reduced myocardial infarct size and preserved systolic and diastolic performance. Intravenous MSC-CM treatment after myocardial infarction increases capillary density and preserves cardiac function, probably by increasing myocardial perfusion.
The present study aimed to elucidate the mechanism by which bone marrow mesenchymal stem cells (BMSCs) differentiate into smooth muscle cells (SMCs) in atherosclerosis.
We isolated mouse BMSCs and incubated them in conditioned medium from plaque-derived SMCs (SMC-CM) and analyzed growth factors from media. BMSCs were treated with different media and harvested at continuous time points for investigating the ability to differentiate toward SMCs. Next, BMSCs of green fluorescence protein (GFP) mice were transplanted into apolipoprotein E(-/-) (apoE(-/-)) mice fed on western type diet for 12 weeks. In vivo efficacy of BMSCs was investigated.
After being cultured using SMC-CM, hepatocyte growth factor (HGF) was abundantly secreted into the medium by BMSCs with time. BMSCs had increased expression of HGF receptor c-met and SMC-specific markers while they also displayed SMC characteristic 'hill and valley-like' appearance with an SMC ultra-structure including actin filaments and dense bodies. In vivo-grafted BMSCs aggravated atherosclerotic lesions and inflammation but ameliorated fibrosis in aorta while they displayed higher expression levels of c-met and early SMC-specific markers but not late-stage markers in aorta. They also demonstrated greater secretion of HGF in the aorta of apoE(-/-) mice. Furthermore, when BMSCs were treated with HGF blocking antibody, they lost the ability to differentiate to SMCs.
HGF from local SMCs plays an important role for the differentiation of homing BMSCs.
Human ESC-derived mesenchymal stem cell (MSC)-conditioned medium (CM) was previously shown to mediate cardioprotection during myocardial ischemia/reperfusion injury through large complexes of 50-100 nm. Here we show that these MSCs secreted 50- to 100-nm particles. These particles could be visualized by electron microscopy and were shown to be phospholipid vesicles consisting of cholesterol, sphingomyelin, and phosphatidylcholine. They contained coimmunoprecipitating exosome-associated proteins, e.g., CD81, CD9, and Alix. These particles were purified as a homogeneous population of particles with a hydrodynamic radius of 55-65 nm by size-exclusion fractionation on a HPLC. Together these observations indicated that these particles are exosomes. These purified exosomes reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury. Therefore, MSC mediated its cardioprotective paracrine effect by secreting exosomes. This novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair.
Restenosis following vascular injury remains a pressing clinical problem. Mesenchymal stem cells (MSCs) promise as a main actor of cell-based therapeutic strategies. The possible therapeutic role of MSCs in vascular stenosis in vivo has been poorly investigated so far. We tested the effectiveness of allogenic bone marrow-derived MSCs in reduction of stenosis in a model of rat carotid arteriotomy. MSCs were expanded in vitro retaining their proliferative and differentiation potentiality. MSCs were able to differentiate into adipocyte and osteocyte mesenchymal lineage cells, retained specific antigens CD73, CD90, and CD105, expressed smooth muscle alpha-actin, were mainly in proliferative phase of cell cycle and showed limited senescence. WKY rats were submitted to carotid arteriotomy and to venous administration with 5 x 10(6) MSCs. MSCs in vivo homed in injured carotids since 3 days after arteriotomy but not in contralateral uninjured carotids. Lumen area in MSC-treated carotids was 36% greater than in control arteries (P = 0.016) and inward remodeling was limited in MSC-treated carotids (P = 0.030) 30 days after arteriotomy. MSC treatment affected the expression level of inflammation-related genes, inducing a decrease of IL-1beta and Mcp-1 and an increase of TGF-beta in injured carotids at 3 and 7 days after arteriotomy (P < 0.05). Taken together, these results indicate that allogenic MSC administration limits stenosis in injured rat carotids and plays a local immunomodulatory action.
Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers
- Skog