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The homing mechanism of MSCs. Schematic summarizing the molecular mechanisms facilitating each step of MSC homing
Source publication
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver th...
Citations
... Mesenchymal stem cells (MSCs), particularly those derived from bone marrow (BMSCs), have garnered significant attention as potential therapeutic agents for a variety of fibrotic diseases. Their appeal lies in their capacity for multidirectional differentiation, robust proliferative abilities, minimal immunogenicity, potent tissue repair capabilities, and intrinsic chemotactic homing properties [4,5]. BMSCs have been documented to navigate to sites of injury and facilitate the structural and functional restitution of tissues and organs via paracrine actions in conditions such as post-infarction fibrosis, cirrhosis, and renal fibrosis [6,7]. ...
Purpose
This study aimed to evaluate the potential of astragalus polysaccharide (APS) pretreatment in enhancing the homing and anti-peritoneal fibrosis capabilities of bone marrow mesenchymal stromal cells (BMSCs) and to elucidate the underlying mechanisms.
Methods
Forty male Sprague-Dawley rats were allocated into four groups: control, peritoneal dialysis fluid (PDF), PDF + BMSCs, and PDF + APSBMSCs (APS-pre-treated BMSCs). A peritoneal fibrosis model was induced using PDF. Dil-labeled BMSCs were administered intravenously. Post-transplantation, BMSC homing to the peritoneum and pathological alterations were assessed. Stromal cell-derived factor-1 (SDF-1) levels were quantified via enzyme-linked immunosorbent assay (ELISA), while CXCR4 expression in BMSCs was determined using PCR and immunofluorescence. Additionally, a co-culture system involving BMSCs and peritoneal mesothelial cells (PMCs) was established using a Transwell setup to examine the in vitro effects of APS on BMSC migration and therapeutic efficacy, with the CXCR4 inhibitor AMD3100 deployed to dissect the role of the SDF-1/CXCR4 axis and its downstream impacts.
Results
In vivo and in vitro experiments confirmed that APS pre-treatment notably facilitated the targeted homing of BMSCs to the peritoneal tissue of PDF-treated rats, thereby amplifying their therapeutic impact. PDF exposure markedly increased SDF-1 levels in peritoneal and serum samples, which encouraged the migration of CXCR4-positive BMSCs. Inhibition of the SDF-1/CXCR4 axis through AMD3100 application diminished BMSC migration, consequently attenuating their therapeutic response to peritoneal mesenchyme-to-mesothelial transition (MMT). Furthermore, APS upregulated CXCR4 expression in BMSCs, intensified the activation of the SDF-1/CXCR4 axis’s downstream pathways, and partially reversed the AMD3100-induced effects.
Conclusion
APS augments the SDF-1/CXCR4 axis’s downstream pathway activation by increasing CXCR4 expression in BMSCs. This action bolsters the targeted homing of BMSCs to the peritoneal tissue and amplifies their suppressive influence on MMT, thereby improving peritoneal fibrosis.
... The arrival of a certain number of MSCs in the damaged tissue is a prerequisite for their active function, The homing of MSCs targeting damaged tissue is key to MSC therapy for various inflammatory diseases, including IBD. 89 So far, only a few studies have studied the aggregation of MSCs in intestinal epithelial tissue, and some of these studies have elucidated homing patterns of intravenous MSC in animal models. MSC homing refers to the directional movement of MSC to the damaged tissue site under the influence of various factors and the replacement of damaged cells in the tissue site. ...
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
... The homing property of UC-MSCs is the key to their direct participation in the repair of skin injury. Many animal experiments have confirmed that when there is injury in the body, transplanted UC-MSCs can migrate to the injured site, differentiate, and replace injured cells using the chemotaxis of the injured tissue microenvironment [47][48][49] . However, with the deepening of the research, the view that MSCs differentiate and replace injured cells is no longer supported. ...
Aging is the main cause of many degenerative diseases. The skin is the largest and the most intuitive organ that reflects the aging of the body. Under the interaction of endogenous and exogenous factors, there are cumulative changes in the structure, function, and appearance of the skin, which are characterized by decreased synthesis of collagen and elastin, increased wrinkles, relaxation, pigmentation, and other aging characteristics. skin aging is inevitable, but it can be delayed. The successful isolation of mesenchymal stromal cells (MSC) in 1991 has greatly promoted the progress of cell therapy in human diseases. The International Society for Cellular Therapy (ISCT) points out that the MSC is a kind of pluripotent progenitor cells that have self-renewal ability (limited) in vitro and the potential for mesenchymal cell differentiation. This review mainly introduces the role of perinatal umbilical cord-derived MSC(UC-MSC) in the field of skin rejuvenation. An in-depth and systematic understanding of the mechanism of UC-MSCs against skin aging is of great significance for the early realization of the clinical transformation of UC-MSCs. This paper summarized the characteristics of skin aging and summarized the mechanism of UC-MSCs in skin rejuvenation reported in recent years. In order to provide a reference for further research of UC-MSCs to delay skin aging.
... However, the main method of MSCs transplantation, peripheral intravenous injection, results in approximately 80 % of MSCs being distributed in the lungs. This quick recognition and elimination by the immune system, along with the difficulty of enriching MSCs in target organs, leads to shortened retention in vivo and greatly limits their therapeutic effectiveness [22,23]. Therefore, there is an urgent need for new delivery technologies, such as cell carriers and modified cells, to reduce elimination, prolong in vivo retention, and enhance organ targeting. ...
Cirrhosis is an aggressive disease, and over 80 % of liver cancer patients are complicated by cirrhosis, which lacks effective therapies. Transplantation of mesenchymal stem cells (MSCs) is a promising option for treating liver cirrhosis. However, this therapeutic approach is often challenged by the low homing ability and short survival time of transplanted MSCs in vivo. Therefore, a novel and efficient cell delivery system for MSCs is urgently required. This new system can effectively extend the persistence and duration of MSCs in vivo. In this study, we present novel porous microspheres with microfluidic electrospray technology for the encapsulation of bone marrow-derived MSCs (BMSCs) in the treatment of liver cirrhosis. Porous microspheres loaded with BMSCs (Mi-BMSCs) exhibit good biocompatibility and demonstrate better anti-inflammatory properties than BMSCs alone. Mi-BMSCs significantly increase the duration of BMSCs and exert potent anti-inflammatory and anti-fibrosis effects against CCl4 and TAA-induced liver cirrhosis by targeting the TGF-β/Smad signaling pathway to ameliorate cirrhosis, which highlight the potential of Mi-BMSCs as a promising therapeutic approach for early liver cirrhosis.
... Other molecules involved in MSCs migration to the liver include hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule-1 (ICAM-1). Once MSCs have migrated to the liver, they can differentiate into hepatocytes through a process known as transdifferentiation [75,76]. ...
Hepatitis is a significant global public health concern, with viral infections being the most common cause of liver inflammation. Antiviral medications are the primary treatments used to suppress the virus and prevent liver damage. However, the high cost of these drugs and the lack of awareness and stigma surrounding the disease create challenges in managing hepatitis. Stem cell therapy has arisen as a promising therapeutic strategy for hepatitis by virtue of its regenerative and immunomodulatory characteristics. Stem cells have the exceptional capacity to develop into numerous cell types and facilitate tissue regeneration, rendering them a highly promising therapeutic avenue for hepatitis. In animal models, stem cell therapy has demonstrated worthy results by reducing liver inflammation and improving liver function. Furthermore, clinical trials have been undertaken to assess the safety and effectiveness of stem cell therapy in individuals with hepatitis. This review aims to explore the involvement of stem cells in treating hepatitis and highlight the findings from studies conducted on both animals and humans. The objective of this review is to primarily concentrate on the ongoing and future clinical trials that assess the application of stem cell therapy in the context of hepatitis, including the transplantation of autologous bone marrow-derived stem cells, human induced pluripotent stem cells, and other mesenchymal stem cells. In addition, this review will explore the potential merits and constraints linked to stem cell therapy for hepatitis, as well as its prospective implications in the management of this disease.
... Although MSCs are effective in treating liver diseases, poor homing at the injury site is the major limitation of MSCbased cell therapy (Yuan et al., 2022). As homing is dependent on an interaction between chemokine and its receptor present on the cell surface (Wang et al., 2017), gene modification of the chemokine receptor in the MSCs was hypothesized to be an effective therapeutic strategy for improved engraftment. ...
Aims: Hepatic fibrosis is the pathological change during chronic liver diseases (CLD) that turns into cirrhosis if not reversed timely. Allogenic mesenchymal stem cell (MSC) therapy is an alternative to liver transplantation for CLD. However, poor engraftment of the transplanted MSCs limits their therapeutic efficacy. MSCs express chemokine receptors that regulate their physiology. We observed several-fold increased expressions of Cxcl3 and decreased expression of Mmp13 in the fibrotic liver. Therefore, we bioengineered MSCs with stable overexpression of Cxcr2 (CXCL3-cognate receptor) and Mmp13, collagenase (MSCGFPCxcr2-Mmp13). Results: The CXCL3/CXCR2 axis significantly increased migration through the activation of AKT/ERK/mTOR signaling. These bioengineered MSCs transdifferentiated into hepatocyte-like cells (MSCGFPCxcr2-Mmp13-HLCs) that endured the drug-/hepatotoxicant-induced toxicity by significantly increasing the antioxidants-Nrf2 and Sod2, while decreasing the apoptosis-Cyt C, Casp3, Casp9, and drug-metabolizing enzyme-Cyp1A1, Cyp1A2, Cyp2E1 markers. Therapeutic transplantation of MSCGFPCxcr2-Mmp13 abrogated AAP-/CCl4-induced hepatic fibrosis in mice by CXCR2-mediated targeted engraftment and MMP-13-mediated reduction in collagen. Mechanistically, induction of CXCL3/CXCR2 axis-activated mTOR-p70S6K signaling led to increased targeted engraftment and modulation of the oxidative stress by increasing the expression and activity of nuclear Nrf2 and SOD2 expression in the regenerated hepatic tissues. A marked change in the fate of transplanted MSCGFPCxcr2-Mmp13 toward hepatocyte lineage demonstrated by co-immunostaining of GFP/HNF4α along with reduced COL1α1 facilitated the regeneration of the fibrotic liver. Innovation and Conclusions: Our study suggests the therapeutic role of allogenic Cxcr2/Mmp13-bioengineered MSC transplantation decreases the hepatic oxidative stress as an effective translational therapy for hepatic fibrosis mitigation-mediated liver regeneration.
... The utilization of autologous mesenchymal stem cells (MSCs) offers a potential solution for mitigating postoperative symptoms, including immunological rejection, as well as reducing the detrimental effects and extended recovery time associated with extensive surgical procedures. Additionally, this approach can help alleviate the financial burden of increased hospital medical bills [5]. ...
... These findings provide evidence that the transplanted mesenchymal stem cells underwent a sequential differentiation process, initially transforming into immature liver cells and subsequently maturing into liver-like cells. This differentiation process was found to be dynamic in nature [5]. Fibrosis and liver failure are caused by immune regulatory imbalances. ...
... Exogenous MSCs transplanted into the body are captured by the target tissue's circulatory system and migrate via vascular endothelial cells. Damaged ischemic tissues attract MSCs, allowing them to preferentially cure the damage [5]. ...
Stem cell therapy is increasingly recognized as an innovative and transformative approach in the field of medicine, with the potential to address tissue damage and manage intricate medical conditions. The utilization of induced pluripotent stem cells (iPSCs) presents a potential avenue for cardiac regeneration in the context of cardiovascular ailments, such as myocardial infarctions. Liver regeneration techniques utilizing mesenchymal stem cells (MSCs) are being offered as potential solutions for end-stage liver failure. Furthermore, stem cell therapy is regarded as a promising intervention for neurodegenerative disorders and ocular conditions, with disease-specific induced pluripotent stem cells (iPSCs) emerging as a frontrunner in prospective therapeutic approaches. The objective of this study is to investigate the advancements made in stem cell therapy research for the diseases mentioned above. It will involve a comprehensive analysis of the mechanisms and principles underlying stem cell treatment in these areas, as well as an examination of the factors that impede the progress of stem cell therapy. Additionally, this paper will offer insights into potential future directions for development in this field.
... 6,7 In recent years, mesenchymal stem cells (MSCs) differentiated into hepatocytes have been considered as an effective alternative treatment for liver disease. [8][9][10] MSCs have several advantages, including wide availability, multipotent differentiation, low immunogenicity, and immunomodulatory properties, 11,12 which can be obtained from various sources such as bone marrow, umbilical cord, placenta, and adipose tissue. [13][14][15] Human adipose tissue-derived mesenchymal stem cells (hADMSCs) are nontumorigenic, ethically acceptable, minimally invasive, and easy to isolate. ...
Hepatocyte-like cells (HLCs) that are differentiated from mesenchymal stem cells (MSCs) provide a valuable resource for drug screening and cell-based regeneration therapy. Differentiating HLCs into 3D spheroids enhances their phenotypes and functions. However, the molecular mechanisms underlying MSCs hepatogenic differentiation are not fully understood. In this study, we generated HLCs from human adipose-derived mesenchymal stem cells (hADMSCs) in both 2D and 3D cultures. We performed an acetyl-proteomics assay on the HLCs derived from both 2D and 3D differentiation and identified a differential change in H3K56 acetylation between the 2 differentiated cells. Our findings revealed that 3D differentiation activated ALB gene transcription by increasing the acetylation level of H3K56, thereby enhancing the phenotypes and functions of HLCs and further promoting their maturation. Notably, inhibiting p300 reduced the acetylation level of H3K56 during hepatogenic differentiation, leading to decreased phenotypes and functions of HLCs, whereas activation of p300 promoted hepatogenic differentiation, suggesting that p300 plays a critical role in this process. In summary, our study demonstrates a potential mechanism through which 3D spheroids differentiation facilitates hADMSCs differentiation into HLCs by promoting p300-mediated H3K56 acetylation, which could have significant clinical applications in liver regeneration and disease modeling.
... Stem cell therapy has emerged as a widely used approach for treating various diseases, and the therapeutic outcome depends on the efficient homing of transplanted cells that can self-renew and differentiate into niche cells essential for stem cell function (20)(21)(22). DPCs and DSCs are readily accessible and abundant sources of autologous cells containing numerous mesenchymal stem cells (MSCs) (23,24), suggesting that transplantation of these cells is a promising therapeutic strategy for hair loss. However, the homing behavior of these cells has yet to be systematically investigated. ...
Hair loss is a debilitating condition associated with the depletion of dermal papilla cells (DPCs), which can be replenished by dermal sheath cells (DSCs). Hence, strategies aimed at increasing the population of DPCs and DSCs hold great promise for the treatment of hair loss. In this study, we demonstrated that introducing exogenous DPCs and DSCs (hair follicle mesenchymal stem cells) could effectively migrate and integrate into the dermal papilla and dermal sheath niches, leading to enhanced hair growth and prolonged anagen phases. However, the homing rates of DPCs and DSCs were influenced by various factors, including recipient mouse depilation, cell passage number, cell dose, and immune rejection. Through in vitro and in vivo experiments, we further discovered that the CXCL13/CXCR5 pathway mediated the homing of DPCs and DSCs into hair follicle niches. This study underscores the potential of cell-based therapies for hair loss by targeted delivery of DPCs and DSCs to their respective niches, and sheds light on the intriguing concept that isolated mesenchymal stem cells can home back to their original niche microenvironment.
... Mesenchymal stem cells (MSCs) are mainly derived from the early developmental mesoderm and widely exist in multiple body tissues such as the dermis (skin), synovial fluid, periosteum, blood, placenta, amniotic fluid, chorionic villi, muscle, dental pulp, breast milk, umbilical cords, and bone marrow [8][9][10]. MSCs are getting international consensus in the treatment of various tissue-damaging diseases due to their high self-renewal capacity and multi-directional differentiation potential [11,12]. ...
Aim
Although the efficacy and safety of mesenchymal stem cell therapy for liver cirrhosis have been demonstrated in several studies. Clinical cases of mesenchymal stem cell therapy for patients with liver cirrhosis are limited and these studies lack the consistency of treatment effects. This article aimed to systematically investigate the efficacy and safety of mesenchymal stem cells in the treatment of liver cirrhosis.
Method
The data source included PubMed/Medline, Web of Science, EMBASE, and Cochrane Library, from inception to May 2023. Literature was screened by the PICOS principle, followed by literature quality evaluation to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Outcome indicators of the assessment included liver functions and adverse events. Statistical analysis was performed using Review Manager 5.4.
Results
A total of 11 clinical trials met the selection criteria. The pooled analysis' findings demonstrated that both primary and secondary indicators had improved. Compared to the control group, infusion of mesenchymal stem cells significantly increased ALB levels in 2 weeks, 1 month, 3 months, and 6 months, and significantly decreased MELD score in 1 month, 2 months, and 6 months, according to a subgroup analysis using a random-effects model. Additionally, the hepatic arterial injection favored improvements in MELD score and ALB levels. Importantly, none of the included studies indicated any severe adverse effects.
Conclusion
The results showed that mesenchymal stem cell was effective and safe in the treatment of liver cirrhosis, improving liver function (such as a decrease in MELD score and an increase in ALB levels) in patients with liver cirrhosis and exerting protective effects on complications of liver cirrhosis and the incidence of hepatocellular carcinoma. Although the results of the subgroup analysis were informative for the selection of mesenchymal stem cells for clinical treatment, a large number of high-quality randomized controlled trials validations are still needed.
