Cardiomyocyte Regeneration

Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas; Field, Loren J.; Fleischmann, Bernd K.; Frisén, Jonas; Giacca, Mauro; Hare, Joshua M.; Houser, Steven R.; Lee, Richard T.; Marbán, Eduardo; Martin, James F.; Molkentin, Jeffery D.; Murry, Charles E.; Riley, Paul R.; Ruiz‐Lozano, Pilar; Sadek, Hesham A.; Sussman, Mark A.; Hill, Joseph A.

doi:10.1161/circulationaha.117.029343

Cited by 415 publications

(219 citation statements)

References 66 publications

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“…MSCs promote myocardial regeneration via several mechanisms, including direct differentiation and stimulation of endogenous cardiomyocyte cell cycling (3,32). Additionally, MSCs secrete an array of growth factors, cytokines, metalloproteinases, and exosomes that trigger endogenous repair mechanisms through paracrine signaling (33–35).…”

Section: Discussionmentioning

confidence: 99%

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

Natsumeda

Florea

Rieger

et al. 2017

Journal of the American College of Cardiology

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Background The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). Objective We tested the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. Methods Gottingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of either allo-MSC + allo-CSC (ACCT: 200 million MSCs/1 million CSCs, n=7), 200 million allo-MSC (n=8), 1 million allo-CSC (n=4), or placebo (Plasma-Lyte A, n=6)]. Swine were assessed by cardiac magnetic resonance imaging (cMR) and pressure volume catheterization. Immune response was tested by histological analyses. Results Both ACCT and allo-MSCs reduced scar size by −11.1±4.8%, (p=0.012) and −9.5±4.8 (p=0.047), respectively. Only ACCT, but not MSC or CSC, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure volume relation (+0.98±0.41 mmHg/mL, p=0.016) The ACCT group had more phospho-histone H3 (pHH3)+ (a marker of mitosis) cardiomyocytes (p=0.04), and non-cardiomyocytes (p=0.0002) compared to the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC swine contained immunotolerant CD3+/CD25+/FoxP3 regulatory T cells (p<0.0001). Histologic analysis showed absent to low grade inflammatory infiltrates without cardiomyocyte necrosis. Conclusion ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunological reaction. Clinical translation to humans is warranted.

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Section: Discussionmentioning

confidence: 99%

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

Natsumeda

Florea

Rieger

et al. 2017

Journal of the American College of Cardiology

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“…The numbers of cardiomyocytes generated by c-kit + cells, as quantified from histological quantifications, or from isolated cardiomyocytes (<0.1%), are too low to give rise to meaningful regeneration. 40 A second limitation to our study is the lack of identifying a specific subpopulation of c-kit + cells that is pre-destined to become cardiomyocytes. If less than 1% of c-kit + cells are predestined to become cardiomyocytes, we may have missed identification of this small population of c-kit + cells by sequencing ‘only’ 400 cells, or potentially due to size exclusion based on single cell capture chip.…”

Section: Discussionmentioning

confidence: 99%

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit ⁺ Cells

et al. 2017

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Background Although cardiac c-kit+ cells are being tested in clinical trials, the circumstances that determine lineage differentiation of c-kit+ cells in vivo are unknown. Recent findings suggest endogenous cardiac c-kit+ cells rarely contribute cardiomyocytes to the adult heart. We assessed whether various pathological stimuli differentially affect the eventual cell fates of c-kit+ cells. Methods We employed single cell sequencing and genetic lineage tracing of c-kit+ cells to determine whether various pathologic stimuli would result in different fates of c-kit+ cells. Results Single cell sequencing of cardiac CD45−c-kit+ cells showed innate heterogeneity, indicative of the existence of vascular and mesenchymal c-kit+ cells in normal hearts. Cardiac pressure overload resulted in a modest increase in c-kit derived cardiomyocytes with significant increases in the numbers of endothelial cells and fibroblasts. Doxorubicin-induced (DOX) acute cardiotoxicity did not increase c-kit derived endothelial cell fates but instead induced cardiomyocyte differentiation. Mechanistically, DOX induced DNA damage in c-kit+ cells resulted in expression of p53. Inhibition of p53 blocked cardiomyocyte differentiation in response to DOX, while the small molecule RITA induced stabilization of p53 was sufficient to increase c-kit derived cardiomyocyte differentiation. Conclusion These results demonstrate that different pathologic stimuli induce different cell fates of c-kit+ cells in vivo. Although the overall rate of cardiomyocyte formation from c-kit+ cells is still below clinically relevant levels, we show that p53 is central to the ability of c-kit+ cells to adopt cardiomyocyte fates, which could lead to the development of strategies to preferentially generate cardiomyocytes from c-kit+ cells.

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“…About a decade later, this work was translated to the clinic, with phase I clinical trials in patients [10,11]. As the field progressed, a paradigm change occurred as scientists started to realize that the injected cells hardly form any new cardiac tissue but instead promote endogenous repair via paracrine mechanisms [12]. In 2017, Nature Biotechnology expressed a severe concern on the none-to-marginal benefits of cardiac cell therapy trials and argued that cardiac cell therapy is “far from getting approval” and “much more preclinical data needs to be performed before any new clinical trials”[13].…”

Section: Obtaining Cells and Tissues From The Naturementioning

confidence: 99%

Body builder: from synthetic cells to engineered tissues

Ogle

Cheng

2018

Current Opinion in Cell Biology

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It is estimated that 18 Americans die every day waiting for an organ donation. And even if a patient receives the organ that s/he needs, there is still >10% chance that the new organ will not work. The field of tissue engineering and regenerative medicine aims to actively use a patient's own cells, plus biomaterials and factors, to grow specific tissues for replacement or to restore normal functions of that organ, which would eliminate the need for donors and the risk of alloimmune rejection. In this review, we summarized recent advances in fabricating synthetic cells, with a specific focus on their application to cardiac regenerative medicine and tissue engineering. At the end, we pointed to challenges and future directions for the field.

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Cardiomyocyte Regeneration

Cited by 415 publications

References 66 publications

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit ⁺ Cells

Body builder: from synthetic cells to engineered tissues

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Cardiomyocyte Regeneration

Cited by 415 publications

References 66 publications

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit + Cells

Body builder: from synthetic cells to engineered tissues

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Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit ⁺ Cells