Mesenchymal Stem Cells: Mechanisms of Immunomodulation and Homing

Yagi, Hiroshi; Soto-Gutiérrez, Alejandro; Parekkadan, Biju; Kitagawa, Yuko; Tompkins, Ronald G.; Kobayashi, Naoya; Yarmush, Martin L.

doi:10.3727/096368910x508762

Cited by 602 publications

(533 citation statements)

References 112 publications

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“…Generally, contact-dependent mechanisms and soluble factors, including 2,3-dioxygenase, prostaglandin-E2, nitric oxide, TGF-b, and hepatocyte growth factor, are thought to collaborate to induce MSC-mediated immunosuppressive effects [64,65]. Moreover, IL-10 has been reported to be involved in MSCmediated immune regulation.…”

Section: Discussionmentioning

confidence: 99%

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Cheng

Xiao-cun

et al. 2015

Stem Cells and Development

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Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1 · 10 6 iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival ( > 100 days). Histopathological analysis revealed that iPSCMSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4 + and CD8 + T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-g was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-b was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSCMSCs in islet transplantation.

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Section: Discussionmentioning

confidence: 99%

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Cheng

Xiao-cun

et al. 2015

Stem Cells and Development

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“…The immunomodulatory property of MSCs were discovered more than a decade ago (Bartholomew et al, 2002;Gotherstrom et al, 2003;Le Blanc et al, 2003). Immunomodulation of MSCs can occur via different mechanisms; the most common mechanism occurs via cytokine signals (released by MSCs); the cytokines include IFN-gamma, TNF-alpha, IL-1 beta, and IL-2 (De Miguel et al, 2012;English, 2013;Yagi et al, 2010). These cytokines efficiently inhibit T cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord-derived stem cells (ModulatistTM) show strong immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived mesenchymal stem cells

Pham¹,

Vu²,

Phan³

2016

Biomed Res Ther

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Abstract-Introduction:Mesenchymal stem cells (MSCs) show great promise in regenerative medicine. Clinical applications of MSCs have recently increased significantly, especially for immune diseases. Autologous transplantation is considered a safe therapy. However, its main disadvantages are poor stability and quality of MSCs from patient to patient, and labor-intensive and time-consuming culture procedures. Therefore, allogeneic MSC transplantation has recently emerged as a potential replacement for autologous transplantation. "Off the shelf" MSC products, or socalled "stem cell drugs", have rapidly developed; these products have already been approved in various countries, including Canada, Korea and Japan. This study aims to evaluate a new stem cell product or "drug", termed Modulatist TM , derived from umbilical cord mesenchymal stem cells (UCMSCs), which have strong immunomodulatory properties, compared to bone marrow-derived MSCs (BMMSCs) or adipose tissue-derived stem cells (ADSCs). Methods: Modulatist TM was produced from MSCs derived from whole umbilical cord (UC) tissue (which includes Wharton's jelly and UC), according to GMP compliant procedures. Bone marrow-and adipose tissue-derived MSCs were isolated and proliferated in standard conditions, according to GMP compliant procedures. Immunomodulation mediated by MSCs was assessed by allogenic T cell suppression and cytokine release; role of prostaglandin E2 in the immunomodulation was also evaluated. Results: The results showed that Modulatist TM exhibited stronger immunomodulation than BMMSC and ADSC in vitro. Modulatist TM strongly suppressed allogeneic T cells proliferation and decreased cytokine production, compared to BMMSCs and ADSCs. Conclusion: Modulatist TM is a strong immunomodulator and promising MSC product. It may be useful to modulate or treat autoimmune diseases.

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“…hMSCs displayed an ability to migrate from the gel in response to a serum stimulus over seven days in a sustained manner. MSCs have been shown to home to sites of injury and inflammation [38]. Therefore it may be possible for encapsulated cells to migrate from the gel in response to cues derived from the necrosis of ischemic tissues.…”

Section: Discussionmentioning

confidence: 99%

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

Hastings

Kelly

Murphy

et al. 2012

Journal of Controlled Release

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Critical limb ischemia (CLI) is a debilitating ischemic disease caused by vascular occlusion. Pro-angiogenic therapeutics have the potential to produce collateral vasculature, delaying or negating the need for amputation or invasive revascularisation. Thermoresponsive hydrogels can provide an in situ depot for the sustained release of drugs and provide protection and cohesion for encapsulated cells. Human Mesenchymal Stem Cells (hMSCs) have demonstrated strong angiogenic potential in vitro and angiogenic efficacy in vivo. Desferrioxamine (DFO), a pharmacological activator of the pro-angiogenic hypoxia inducible factor-1α pathway, has shown pro-angiogenic efficacy in vivo. This study combined hMSCs and DFO with a thermoresponsive chitosan/β-glycerophosphate β-e to nction as an in ecta e m timoda pro-an io enic therape tic or the treatment o his e nderwent a thermo e ation e innin at and provided a sustained, biologically active release of DFO over the space of seven days, whilst permitting the survival, proliferation and migration of encapsulated hMSCs. hMSCs encapsulated in gel containing a 100µM concentration of DFO displayed an upregulation in VEGF expression. The combination of hMSCs and DFO within the gel resulted in a synergistic enhancement in bioactivity, as measured by increased VEGF expression in gel-exposed human umbilical vein endothelial cells. This formulation displays significant potential as an injectable pro-angiogenic therapeutic for the treatment of CLI.

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Mesenchymal Stem Cells: Mechanisms of Immunomodulation and Homing

Cited by 602 publications

References 112 publications

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Umbilical cord-derived stem cells (ModulatistTM) show strong immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived mesenchymal stem cells

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

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