Relative Roles of Direct Regeneration Versus Paracrine Effects of Human Cardiosphere-Derived Cells Transplanted Into Infarcted Mice

By I. Chimenti, R. Smith, Tao-Sheng Li, G. Gerstenblith, E. Messina, A. Giacomello, Eduardo Marbán. Circulation Research, 2010

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Rationale: Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair. Objective: Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells. Methods and Results: In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects. Conclusions: Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as “role models,” recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration.

Subfields: Genetics, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/2fb2e4604835a0c0855409525e70870a57ec17be

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Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. (2014, background): “Taken together, these results indicate that exosomes are the predominant component of EVs secreted by CPCs.”
Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. (2013, positive): “Most studies suggest that MSCs mediate their therapeutic efficacy through the secretion of paracrine factors (Chimenti et al., 2010; Gnecchi et al., 2005, 2006, 2008).”
Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy (2014, background): “…and Eduardo Marbán1,* 1Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA *Correspondence: eduardo.marban@cshs.org http://dx.doi.org/10.1016/j.stemcr.2014.04.006 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).”