Abstract 12847: Cardiogenesis Using Bone Marrow Derived iPS Cells and Their Derivative Cardiac Progenitor Cells
Background —The strategy to reprogram somatic stem cells to pluripotency status has provided an alternative source of stem cells with ES cell like differentiation characteristics. We hypothesized that multipotent bone marrow cells (BMCs) would be excellent candidates for reprogramming and the resultant BMC-derived iPS cells (BM-iPSCs) would be more effective for cardiogenesis to repair the infarcted heart.
Methods and Results—BMCs from young, male, Oct4-GFP transgenic mice were reprogrammed by retroviral transduction with Oct4, Sox2, Klf4, and c-Myc stemness factors. BM-iPSCs thus generated displayed phenotypic characteristics identical to mouse ES cells including morphology, gene and miRNA expression, and surface antigens. Using standard embryoid body differentiation protocol, BM-iPSCs formed spontaneously beating cardiac progenitors which expressed cardiac specific transcription factors and protein markers such as Gata4, Mef2c, Nkx2.5, myosin heavy chain, troponin-I, and troponin-T. Transmission electron microscopy showed ultra structural characteristics of cardiac like cells. Intramyocardial delivery of BM-iPSCs (group-1) and their derivative cardiac like cells (group-2) in a mouse model of acute myocardial infarction showed extensive survival and engraftment of the transplanted cells at 4 weeks with resultant attenuation of infarct size (p<0.001 vs DMEM injected control group-3; n=4). Engraftment of BM-iPSC derived cardiac progenitors was without tumorgenesis as compared to 21% animals which developed tumors with BM-iPSCs. Furthermore, angiogenesis was significantly improved in groups-1 and 2 as compared to group-3 (p<0.05 peri-infarct; p<0.001 infarct). Transthoracic echocardiography revealed significantly improved indices of cardiac contractility (ejection fraction p<0.001 and fractional shortening p<0.001 vs control; n=7) in group-2 animal hearts as compared to non-treated group-3 animals.
Conclusions—BMCs were successfully reprogrammed into iPS cells that displayed ESC like characteristics and differentiated into spontaneously beating cardiomyocytes. Cardiac progenitors derived from BM-iPSCs repopulated the infarcted heart without tumorgenesis and improved global cardiac function.
- © 2011 by American Heart Association, Inc.