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

Abstract

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.

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…The availability of these well-characterized heart progenitor cells allows for a direct examination of their biological function and specific pathway that drives cardiogenesis in the developmental stage and regeneration infarcted myocardium (6,30,37). Epigenetic intervention and/or HDAC inhibition have been recently identified as the critical determinant for cell programming in in vitro studies (16, 42, 44).…”

The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function

“…While direct differentiation into working heart tissue provides a small portion of CSCmediated benefits, emerging evidence suggests that the local production of cardio-protective and pro-angiogenic cytokines plays an important role in the transplant associated outcomes [6,22,23]. To ensure that the production of cytokines was not inhibited in encapsulated CSCs, a representative panel of cytokines was profiled within conditioned media collected under stress conditions (1% oxygen tension and low serum media) from adherent, encapsulated and suspended CSCs.…”

Estado actual de la terapia con células madre en el tratamiento de las cardiopatías: An update

“…Es posible aislar y expandir CSC desde biopsias miocárdicas realizada median-te un procedimiento mínimamente invasivo o quirúrgico. Las CSC tendrían un mayor compromiso de diferenciación hacia cardiomiocitos, células musculares lisas y células endoteliales, manteniendo un importante componente paracrino [18][19][20][21][22] . Aún es motivo de investigación si subpoblaciones de estas células (diferenciadas por marcadores moleculares) poseen distintos efectos terapéuticos 20 .…”

“…Las células madre ejercen además un importante efecto paracrino, sintetizando y secretando una amplia variedad de factores de crecimiento y citoquinas con efectos antiapoptóticos (bFGF, IGF-1), proangiogénicos (VEGF) y antifibróticos (TNFα, metaloproteinasas) 6,16,22,28 . El efecto de estas citoquinas explicaría parcialmente la inhibición de apoptosis y fibrosis, la neovascularización y la mejoría del remodelamiento ventricular, reportado en modelos experimentales 24,25,29 .…”