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Mesenchymal stromal cells from human bone marrow (hMSCs) were observed to produce therapeutic benefits in some models for cardiac and vascular injuries but their mode of action was not defined. We tested the effects of hMSCs in models for restricted vascular flow.
We made model for restricted vascular flow produced by permanent ligation of a caroti...
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... of hMSCs in a mouse model of restricted arterial flow. Seven days after ligation of the left common carotid artery, the serum level of MCP-1 protein was elevated in HBSS mice with ligation and was significantly lower in mice in which hMSCs were infused immediately after surgery and on day 6 (100.75.15 pg/mL, n 5, vs. 56.11.86 pg/mL, n 6, p0.05) (Fig. 5). After 14 and 21 days, the levels decreased in the HBSS group with ligation and there was no difference from the control group that was infused with hMSCs on days 0, 6 and 13 (43.20.95 vs. 47.2 1.83, n 6 and 28.21.02 vs.26.30.50, n 5, respectively, n.s.). hMSC administration clearly inhibited the expression of MCP-1 in mouse serum in ...
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... In an atherosclerotic mouse model, the use of skin-derived or human amnion-derived MSCs decreased plaque size in the arteries in vivo Wei et al., 2019). MSCs are implicated in reducing the aggregation of TMϕ in the arterial intima (Shoji et al., 2011), inhibiting the formation of foam cells by elevating the number and function of Tregs in vivo and by decreasing TNFα release . All of these steps require regulation of TMϕ polarization and modulation of the phenotypes in the plaque (Yang et al., 2020). ...
Mesenchymal stromal cells (MSCs) have been widely investigated for regenerative medicine applications, from treating various inflammatory diseases as a cell therapy to generating engineered tissue constructs. Numerous studies have evaluated the potential effects of MSCs following therapeutic administration. By responding to their surrounding microenvironment, MSCs may mediate immunomodulatory effects through various mechanisms that directly (i.e., contact-dependent) or indirectly (i.e., paracrine activity) alter the physiology of endogenous cells in various disease pathologies. More specifically, a pivotal crosstalk between MSCs and tissue-resident macrophages and monocytes (TMφ) has been elucidated using in vitro and in vivo preclinical studies. An improved understanding of this crosstalk could help elucidate potential mechanisms of action (MOAs) of therapeutically administered MSCs. TMφ, by nature of their remarkable functional plasticity and prevalence within the body, are uniquely positioned as critical modulators of the immune system – not only in maintaining homeostasis but also during pathogenesis. This has prompted further exploration into the cellular and molecular alterations to TMφ mediated by MSCs. In vitro assays and in vivo preclinical trials have identified key interactions mediated by MSCs that polarize the responses of TMφ from a pro-inflammatory (i.e., classical activation) to a more anti-inflammatory/reparative (i.e., alternative activation) phenotype and function. In this review, we describe physiological and pathological TMφ functions in response to various stimuli and discuss the evidence that suggest specific mechanisms through which MSCs may modulate TMφ phenotypes and functions, including paracrine interactions (e.g., secretome and extracellular vesicles), nanotube-mediated intercellular exchange, bioenergetics, and engulfment by macrophages. Continued efforts to elucidate this pivotal crosstalk may offer an improved understanding of the immunomodulatory capacity of MSCs and inform the development and testing of potential MOAs to support the therapeutic use of MSCs and MSC-derived products in various diseases.
... These properties make hAMSCs a suitable potential resource for clinical applications (36). The immunomodulatory properties of hAMSCs have been previously identified, including the influence of T-cell proliferation, the inhibition of dendritic cell differentiation and maturation (37), and the inhibition of macrophage-mediated production of inflammatory cytokines (38,39). Therefore, the present study investigated the effect of hAMSCs on the inhibition of the formation and progression of atherosclerotic plaque in apolipoprotein E-knockout (apoE-KO) mice by regulating the function of inflammatory macrophages, suggesting a therapeutic potential of hAMSCs for the treatment of AS. ...
... Our previous study suggested that hAMSCs have a strong paracrine function, which could significantly promote the proliferation and tube formation of endothelial cells (40). Similar experiments on the therapeutic improvement of MSCs without significant engraftment have been reported in various animal models (39,54). Due to the limited time and research Figure 2. Effects of early and late hAMSCs treatment on weight and lipid levels in apolipoprotein E-knockout mice. ...
... Therefore, reducing the aggregation of macrophages and the formation of foam cells in atherosclerotic plaque is essential to control the inflammatory response during AS. According to previous studies, MSCs could reduce the aggregation of macrophages in the arterial intima (39), inhibit the formation of macrophage-foam cells (27), decrease the expression of inflammatory factor TNFα and increase the expression of anti-inflammatory factors such as IL-10 (5). In the present study, hAMSCs treatment was found to decrease the accumulation of macrophages in atherosclerotic plaque. ...
Mesenchymal stem cells (MSCs) show immunosuppressive activities and alleviate atherosclerosis (AS) formation in apolipoprotein E‑knockout (apoE‑KO) mice. Human amnion mesenchymal stem cells (hAMSCs), a particular population of mesenchymal stem cells, have been shown to have immunomodulatory abilities. The present study investigated the effects of hAMSCs treatment on early atherosclerotic plaque formation and the progression of established lesion in apoE‑KO mice. In total, 36 mice were fed with a high‑fat diet. Mice were subjected to hAMSCs‑injection treatment simultaneously with high‑fat diet (early treatment) or after 8 weeks of high‑fat diet (delayed treatment). In each treatment, mice were divided into three groups: i) hAMSCs group with hAMSCs treatment; ii) PBS group injected with PBS; and iii) control group without injection. Histological results showed that the plaque area in the aortic arch of mice was significantly reduced after hAMSCs treatment in the early and delayed treatment groups. In addition, immunohistochemical analysis suggested that the accumulation of macrophages was significantly decreased after hAMSCs treatment. Similarly, the release of the pro‑inflammatory cytokine tumor necrosis factor‑α was also decreased, whereas the release of the anti‑inflammatory cytokine interleukin‑10 was increased. In addition, hAMSCs treatment suppressed the phosphorylation of p65 and inhibitor of κB‑α, suggesting that NF‑κB pathway was involved in the hAMSCs‑mediated suppression of immune response. In conclusion, hAMSCs treatment was effective in reducing immune response, which is the one of the major causes of AS, eventually leading to a significant reduction in size of atherosclerotic lesions.
... 7 Another study reported the therapeutic effects of human MSCs by decreasing the inflammatory response to carotid artery ligation. 8 Exosomes secreted by MSCs have been shown to mediate intercellular communications between these cells and their target cells 9 ; however, the role of MSC-derived exosomes (MSC-Exo) in neointimal hyperplasia remains to be fully elucidated. ...
Intercellular communication between mesenchymal stem cells (MSCs) and their target cells in the perivascular environment is modulated by exosomes derived from MSCs. However, the potential role of exosome‐mediated microRNA transfer in neointimal hyperplasia remains to be investigated. To evaluate the effects of MSC‐derived exosomes (MSC‐Exo) on neointimal hyperplasia, their effects upon vascular smooth muscle cell (VSMC) growth in vitro and neointimal hyperplasia in vivo were assessed in a model of balloon‐induced vascular injury. Our results showed that MSC‐Exo were internalised by VSMCs and inhibited proliferation and migration in vitro. Further analysis revealed that miR‐125b was enriched in MSC‐Exo, and repressed the expression of myosin 1E (Myo1e) by targeting its 3ʹ untranslated region. Additionally, MSC‐Exo and exosomally transferred miR‐125b repressed Myo1e expression and suppressed VSMC proliferation and migration and neointimal hyperplasia in vivo. In summary, our findings revealed that MSC‐Exo can transfer miR‐125b to VSMCs and inhibit VSMC proliferation and migration in vitro and neointimal hyperplasia in vivo by repressing Myo1e, indicating that miR‐125b may be a therapeutic target in the treatment of vascular diseases.
... Radiation exposure causes vascular endothelial dysfunction, which leads to vascular inflammatory and oxidative stress [18]. MSCs have been revealed to have the anti-inflammatory function in the repairing process of vascular injuries [19]. Recently, studies also proved that MSCs provide protection against radiation-induced liver injury and radiation-induced proctitis by antioxidative and anti-inflammatory process to maintain the vascular endothelial function [20,21]. ...
The present study aims to explore the protective effect of human bone marrow mesenchymal stem cells (hBMSCs) on radiation-induced aortic injury (RIAI). hBMSCs were isolated and cultured from human bone marrow. Male C57/BL mice were irradiated with a dose of 18-Gy 6MV X-ray and randomly treated with either vehicle or hBMSCs through tail vein injection with a dose of 10 ³ or 10 ⁴ cells/g of body weight (low or high dose of hBMSCs) within 24 h. Aortic inflammation, oxidative stress, and vascular remodeling were assessed by immunohistochemical staining at 3, 7, 14, 28, and 84 days after irradiation. The results revealed irradiation caused aortic cell apoptosis and fibrotic remodeling indicated by aortic thickening, collagen accumulation, and increased expression of profibrotic cytokines (CTGF and TGF- β ). Further investigation showed that irradiation resulted in elevated expression of inflammation-related molecules (TNF- α and ICAM-1) and oxidative stress indicators (4-HNE and 3-NT). Both of the low and high doses of hBMSCs alleviated the above irradiation-induced pathological changes and elevated the antioxidant enzyme expression of HO-1 and catalase in the aorta. The high dose even showed a better protective effect. In conclusion, hBMSCs provide significant protection against RIAI possibly through inhibition of aortic oxidative stress and inflammation. Therefore, hBMSCs can be used as a potential therapy to treat RIAI.
... However, the effect of BM-MSCs in vascular injury remains to be fully elucidated. Certain studies have demonstrated the capacity of BM-MSCs to restoring the endothelial lining and reduce neointimal formation following injury (6)(7)(8). ...
The present study investigated the contribution of bone marrow-derived mesenchymal stem cells (BM‑MSCs) to neointimal formation, and whether endothelial‑like cells (ELCs) differentiated from BM‑MSCs could attenuate intimal hyperplasia following vascular injury. BM‑MSCs were isolated from rat femurs and tibias and expanded ex vivo. Differentiation into ELCs was induced by cultivation in the presence of 50 ng/ml vascular endothelial growth factor (VEGF). MSCs and ELCs were labeled with BrdU and injected via the femoral vein on the day of a balloon‑induced carotid artery injury. Carotid artery morphology and histology were examined using ultrasound biomicroscopy and immunohistochemistry. Flow cytometry analysis measured CD31 and CD34 expression, and immunofluorescence analysis measured von Willebrand factor and VEGF receptor 2 expression in ELCs. Ultrasound biomicroscopy observed a significantly increased intima‑media thickness in the phosphate‑buffered saline (PBS) and BM‑MSCs groups compared with the ELCs group. Intima/media ratios were significantly reduced in the ELCs group compared with the PBS and BM‑MSCs groups. At 4 weeks of administration, the cells labeled with BrdU were abundantly located in the adventitial region and neointima. MSCs were able to differentiate into ELCs in vitro. Cell therapy with BM‑MSCs was not able to attenuate neointima thickness, however transplantation with ELCs significantly suppressed intimal hyperplasia following vascular injury.
... Human MSCs infused three times into the cardiac left ventricle have also been shown to be effective in reducing the neointima in a mouse model of restricted vascular flow produced by permanent ligation of a carotid artery [65], presumably through a decrease in the inflammatory reaction; findings in agreement with our results in the rat carotid arteriotomy model. An interesting study proposed an alternative local administration of MSCs in porcine saphenous vein grafts through their encapsulation in alginate microbeads (Cell-Beads) [66]. ...
Restenosis is pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall submitted to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, significantly reduced but not eliminated the incidence of restenosis, which remains a clinically relevant problem.
Biomedical research in preclinical animal models of (re)stenosis, despite its limitations, enormously contributed to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease.
Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously discovered. In particular, microRNAs and vascular progenitor cells recently revealed a key role in this pathophysiological process. Also, the advanced, highly-sensitive highthroughput analyses of molecular alterations at transcriptome, proteome and metabolome level occurring in injured vessels in animal models of disease and in human specimens, are serving as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, that could be potentially helpful in the establishment of an early diagnosis and therapy.
This review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable in patients submitted to revascularization procedures.
... The paracrine effect of MSCs was also observed in another study where MSCs inhibited neointimal hyperplasia in a carotid artery ligation model by decreasing the initial inflammation at the lesion area. There was decreased macrophage infiltration into the ligated artery, as well as, decreased serum levels of MCP-1 and 3, seven days after the administration of MSCs [58]. However, here also there was no indication of MSC incorporation into the lesion. ...
... However, here also there was no indication of MSC incorporation into the lesion. This lead the authors to hypothesize that the effect might also be due to the mobilization of endogenous stem cells from the bone marrow to the peripheral circulation, and the mobilized cells accumulate at the area of vascular injury which may modulate the systemic and local inflammatory responses [58]. Similar results were obtained in a wire injury model of rat femoral artery where the adipose derived MSCs potently and significantly inhibited neointimal formation without being integrated in the endothelial layer. ...
Mesenchymal stem cell therapy show great optimism in the treatment of several diseases. MSCs are attractive candidates for cell therapy because of easy isolation, high expansion potential giving unlimited pool of transplantable cells, low immunogenicity, amenability to ex vivo genetic modification, and multipotency. The stem cells orchestrate the repair process by various mechanisms such as transdifferentiation, cell fusion, microvesicles or exosomes and most importantly by secreting paracrine factors. The MSCs release several angiogenic, mitogenic, anti-apoptotic, anti-inflammatory and anti-oxidative factors that play fundamental role in regulating tissue repair in various vascular and cardiac diseases. The therapeutic release of these factors by the cells can be enhanced by several strategies like genetic modification, physiological and pharmacological preconditioning, improved cell culture and selection methods, and biomaterial based approaches. The current review describes the impact of paracrine factors released by MSCs on vascular repair and regeneration in myocardial infarction, restenosis and peripheral artery disease, and the various strategies adopted to enhance the release of these paracrine factors to enhance organ function.
... However, PCR assays did not detect hMSCs in the carotid arteries. Sections of arteries assayed by immunohistochemistry using a human specific antinuclear antibody did not detect human cells in the mouse carotid arteries [19]. These findings showed that the systemic administration of hMSCs decreased neointimal hyperplasia in a mouse model without significant long-term engraftment into the lesion. ...
... Levels of MCP-1 were higher in mice injected with PBS than with hMSCs 24 h before being fed the HF diet for 12 weeks. Our results indicated that serum MCP-1 levels in the mouse model of atherosclerosis were significantly decreased after hMSC administration [19]. Because MCP-1 has direct proatherogenic properties in addition to its ability to amplify the inflammatory cascade, it might have played a major role in inhibiting neointimal hyperplasia after surgery in this experimental model. ...
Bone-marrow-derived cells can generate vascular progenitor cells that contribute to pathological remodeling in models of restenosis after percutaneous coronary intervention (PCI). We created models of vascular injury in mice with bone marrow transplants (BMT) to determine relationships between bone-marrow-derived cells and subsequent biological factors. Mesenchymal stromal cells (MSCs) seemed to inhibit the inflammatory reaction and help stabilize injured vascular regions through mobilizing more endogenous bone-marrow-derived (EBMD) cells to the peripheral circulation. Granulocyte-colony stimulating factor (G-CSF) mobilized more EBMD cells to the peripheral circulation, and they accumulated on the injured side of the vascular lumen. The inflammatory cytokines, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 mobilized EBMD cells that play an important role in the process of neointimal hyperplasia after vascular injury. These factors might comprise a mechanism that alters the transdifferentiation or paracrine capabilities of EBMD cells and are potential targets of treatment for patients with cardiovascular diseases.
... An additional contributory factor may be the paucity of inflammatory cells in NB stroma. In line with this observation, it has been shown in different experimental models that MSCs may have little propensity to localize to injured tissues although exerting paracrine biological effects [50,51]. However, based to the fact that MSCs show different effects on different NB cell lines, we cannot also exclude that the lack of MSC recruitment in NB is likely a cell line specific phenomenon. ...
Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment.
... Vascular injury causes acute systemic inflammation and mobilize s endothelial progenitor cells and endothelial cell colony-forming units. For one thing, it has been thought that circulating endothelial progenitor cells are not affected by acute They also provide enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation (31,32). Intracoronary infusions of MSC improve postischemic left ventricular function and reduce inflammatory signaling via a STAT3dependent mechanism (33). ...
Mesenchymal stem cells (MSC) play a crucial role in endothelial repair after artery injury. The high mobility group box 1 (HMGB1) is a key modulator of the homing of MSC to impaired artery and endothelialization. This study was aimed to determine whether balloon-induced carotid artery injury could be improved by transplantation with MSC modified by HMGB1. MSC were infected by adenoviral serotype 5 encoding recombinant green fluorescent protein (GFP) gene and HMGB1 (ad5GFP-HMGB1). The expression of HMGB1, vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) was detected in MSC using Real-time PCR, Western blot and semi-quantitative immunohistochemical assays. In vivo, reendothelialization was examined in rats subjected to carotid artery injury. The homing of MSC was observed under fluorescence microscopy, and the levels of serum tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) was assessed by ELISA assay. As a result, compared with the MSC group, the expression of HMGB1, VEGF and PCNA was markedly increased, vascular reendothelialization was accelerated, and the levels of serum TNF-α and CRP were decreased in group ad5GFP and ad5GFP-HMGB1. Transplantation of MSC infected with adGFP-HMGB1 strengthened the MSC effect. Taken together, modification of HMGB1 can enhance the protective effects of MSC on balloon-induced carotid artery injury through up-regulation of VEGF and PCNA expression and inhibition of the inflammatory response. HMGB1 in MSC may represent a novel therapeutic target for the treatment of endothelial repair.
