Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice.
BACKGROUND
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.


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.
Chimenti
Isotta
I
Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Smith
Rachel Ruckdeschel
RR
Li
Tao-Sheng
TS
Gerstenblith
Gary
G
Messina
Elisa
E
Giacomello
Alessandro
A
Marbán
Eduardo
E
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012038:Regeneration; D018874:Spheroids, Cellular; D033581:Stem Cell Transplantation; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017077:Culture Media, Conditioned; C066855:HGF protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3