Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury

Zhao, Yuanyuan; Sun, Xiaoxian; Cao, Wenming; Ma, Jie; Sun, Li; Qian, Hui; Zhu, Wei; Xu, Wenrong

doi:10.1155/2015/761643

Cited by 209 publications

(166 citation statements)

References 38 publications

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“…Recent studies have shown that MSC-EV products can efficiently modulate inflammatory disorders in vivo , including rat and mouse models and also human clinical trials 17,21,45-47. Yet, several controversial studies noticed reduced immunosuppressive functions of CM and EVs compared to their parental cells 26,27.…”

Section: Discussionmentioning

confidence: 99%

Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine

Roura²,

et al. 2017

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Undesired immune responses have drastically hampered outcomes after allogeneic organ transplantation and cell therapy, and also lead to inflammatory diseases and autoimmunity. Umbilical cord mesenchymal stem cells (UCMSCs) have powerful regenerative and immunomodulatory potential, and their secreted extracellular vesicles (EVs) are envisaged as a promising natural source of nanoparticles to increase outcomes in organ transplantation and control inflammatory diseases. However, poor EV preparations containing highly-abundant soluble proteins may mask genuine vesicular-associated functions and provide misleading data. Here, we used Size-Exclusion Chromatography (SEC) to successfully isolate EVs from UCMSCs-conditioned medium. These vesicles were defined as positive for CD9, CD63, CD73 and CD90, and their size and morphology characterized by NTA and cryo-EM. Their immunomodulatory potential was determined in polyclonal T cell proliferation assays, analysis of cytokine profiles and in the skewing of monocyte polarization. In sharp contrast to the non-EV containing fractions, to the complete conditioned medium and to ultracentrifuged pellet, SEC-purified EVs from UCMSCs inhibited T cell proliferation, resembling the effect of parental UCMSCs. Moreover, while SEC-EVs did not induce cytokine response, the non-EV fractions, conditioned medium and ultracentrifuged pellet promoted the secretion of pro-inflammatory cytokines by polyclonally stimulated T cells and supported Th17 polarization. In contrast, EVs did not induce monocyte polarization, but the non-EV fraction induced CD163 and CD206 expression and TNF-α production in monocytes. These findings increase the growing evidence confirming that EVs are an active component of MSC's paracrine immunosuppressive function and affirm their potential for therapeutics in nanomedicine. In addition, our results highlight the importance of well-purified and defined preparations of MSC-derived EVs to achieve the immunosuppressive effect.

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Section: Discussionmentioning

confidence: 99%

Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine

Roura²,

et al. 2017

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“…Recently, paracrine mechanisms in adult stem cell therapy following acute myocardial infarction have been postulated, that is, the transplanted stem cells release soluble factors that engage in paracrine-like activity, and contribute to cardiac repair and regeneration37. Administration of exosomes, which are nanometer-sized membranous vesicles released into surrounding bio-fluids, derived from human umbilical cord MSCs improved cardiac systolic function in an acute myocardial infarction model38. Likewise, it is possible that the UCBCs engrafted in other tissues or their differentiated progeny likely release a certain trophic factor(s) and give rise to an unidentified endogenous response to reduce brain injury.…”

Section: Discussionmentioning

confidence: 99%

Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

Nakanishi

Sato

Mizutani

et al. 2017

Sci Rep

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Increasing evidence has suggested that human umbilical cord blood cells (hUCBC) have a favorable effect on hypoxic–ischemic (HI) brain injury. However, the efficacy of using hUCBCs to treat this injury has been variable and the underlying mechanism remains elusive. Here, we investigated its effectiveness using stereological analysis in an allogeneic system to examine whether intraperitoneal injection of cells derived from UCBCs of green fluorescent protein (GFP)-transgenic rats could ameliorate brain injury in neonatal rats. Three weeks after the HI event, the estimated residual brain volume was larger and motor function improved more in the cell-injected rats than in the control (PBS-treated) rats. The GFP-positive cells were hardly detectable in the brain (0.0057% of injected cells) 9 days after injection. Although 60% of GFP-positive cells in the brain were Iba1-positive, none of these were positive for NeuroD or DCX. While the number of proliferating cells increased in the hippocampus, that of activated microglia/macrophages decreased and a proportion of M2 microglia/macrophages increased in the ipsilateral hemisphere of cell-injected rats. These results suggest that intraperitoneal injection of cells derived from UCBCs could ameliorate HI injury, possibly through an endogenous response and not by supplying differentiated neurons derived from the injected stem cells.

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“…Exosomes from human umbilical cord mesenchymal stem cells (hucMSCs) have been reported to promote heart repair following ischemic injury by protecting myocardial cells from apoptosis and promoting cell proliferation and angiogenesis. hucMSCs without exosomes have nearly no effect on cardiac function recovery, suggesting hucMSC-exosome–mediated myocardial repair 85,86 . hucMSC-exosomes promoted wound healing and angiogenesis in vivo , and this pro-angiogenic effect was mediated by Wnt4/β-catenin activation in endothelial cells 87 .…”

Section: Therapeutic Effects Of Exosomes Derived From the Differenmentioning

confidence: 99%

Exosomes Generated From iPSC-Derivatives

Jung

Yang

2017

Circulation Research

146

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Cardiovascular disease (CVD) is the leading cause of death in modern society. The adult heart innately lacks the capacity to repair and regenerate the damaged myocardium from ischemic injury. Limited understanding of cardiac tissue repair process hampers the development of effective therapeutic solutions to treat CVD such as ischemic cardiomyopathy. In recent years, rapid emergence of induced pluripotent stem cells (iPSC) and iPSC-derived cardiomyocytes (iCM) presents a valuable opportunity to replenish the functional cells to the heart. The therapeutic effects of iPSC-derived cells have been investigated in many preclinical studies. However, the underlying mechanisms of iPSC-derived cell therapy are still unclear and limited engraftment of iCMs are well known. One facet of their mechanism is the paracrine effect of the transplanted cells. Microvesicles such as exosomes secreted from the iCMs exert protective effects by transfering the endogenous molecules to salvage the injured neighboring cells by regulating apoptosis, inflammation, fibrosis and angiogenesis. In this review, we will focus on the current advances in the exosomes from iPSC-derivatives and discuss their therapeutic potential in the treatment of CVD.

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Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury

Cited by 209 publications

References 38 publications

Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine

Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine

Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

Exosomes Generated From iPSC-Derivatives

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