Direct Evaluation of Myocardial Viability and Stem Cell Engraftment Demonstrates Salvage of the Injured Myocardium

Kim, Paul J.; Mahmoudi, Morteza; Ge, Xiaohu; Matsuura, Yuka; Toma, Ildikó; Metzler, Scott; Kooreman, Nigel G.; Ramunas, John; Holbrook, Colin; McConnell, Michael V.; Blau, Helen M.; Harnish, Phillip; Rulifson, Eric; Yang, Phillip C.

doi:10.1161/circresaha.116.304668

Cited by 51 publications

(44 citation statements)

References 34 publications

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“…Our MiCMs have shown to improve cardiac function of injured mouse hearts after MI. We observed that the MiCM-derived exosomes exhibited similar functions, such as cardiac-protective role, improving LVEF (left ventricular ejection fraction) and myocardial viability 106,107 . The exosomal cargo contained several up-regulated miRNAs, including miR-92a believed to stimulate endogenous anti-apoptotic, pro-angiogenic, and anti-fibrotic pathways.…”

Section: Therapeutic Effects Of Exosomes Derived From the Differenmentioning

confidence: 77%

Exosomes Generated From iPSC-Derivatives

Jung

Yang

2017

Circulation Research

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143

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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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Section: Therapeutic Effects Of Exosomes Derived From the Differenmentioning

confidence: 77%

Exosomes Generated From iPSC-Derivatives

Jung

Yang

2017

Circulation Research

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143

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“…None of the studies included reported safety end points such as “Major Cardiovascular Adverse Events” (MACE). In 22 of the 34 included groups, immunodeficient mice were used, yet tumor – more precisely teratoma – formation in animals receiving murine PSCs were reported in two of these groups only [21, 22]. …”

Section: Resultsmentioning

confidence: 99%

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Lang

Wolfien

Langenbach

et al. 2017

Cell Physiol Biochem

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Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

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“…This approach uses autologous cells, thus avoiding alloimmune rejection. iPSC-derived cardiomyocytes from human placenta amniotic MSCs engrafted successfully in immunocompetent SVJ mice and improved myocardial viability and cardiac function after MI (77,78). These exosomes transported several upregulated miRNAs, including miR-92a which has been associated with antiapoptotic, proangiogenic, and antifibrotic effects.…”

Section: Cardioprotection By Exosomes From Ipsc-derived Cardiomyocytesmentioning

confidence: 99%

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Barile¹,

Milano²,

Vassalli³

2017

Stem Cell Investig.

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When injected into acutely infarcted rodent or pig hearts, naturally secreted nanovesicles known as exosomes from cardiac-derived progenitor cells (CPCs) reduce scar size and improve cardiac function. In this regard, exosomes fully mimic the benefits of injecting their parent cells. This recognition paves the way to the development of exosome-based, cell-free treatments for heart disease that could possibly supplant cellbased therapies. Mechanisms of benefit of these vesicles are incompletely understood but cytoprotection, stimulation of angiogenesis, induction of antifibrotic cardiac fibroblasts, and modulation of M1/M2 polarization of macrophages infiltrating the infarcted region can all play important roles. Accordingly, the beneficial molecules carried by CPC-secreted exosomes have been identified only in part but cytoprotective and proangiogenic microRNAs (miRNA) and proteins have been described. Besides CPC-secreted exosomes, vesicles released from other cell types including mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iSPCs) have also been associated with cardioprotection. This review aims to discuss recent advances in our understanding of the role of secreted vesicles in cardiac repair, with a focus on CPC-derived exosomes.

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Direct Evaluation of Myocardial Viability and Stem Cell Engraftment Demonstrates Salvage of the Injured Myocardium

Cited by 51 publications

References 34 publications

Exosomes Generated From iPSC-Derivatives

Exosomes Generated From iPSC-Derivatives

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

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