Abstract 14329: Multipotent Cardiovascular Progenitors Derived from Human Pluripotent Stem Cells are Effective for Treating Ischemic Vascular Disease
Cell therapy is an attractive emerging option for the treatment of patients with critical limb ischemia. So far, the results of published clinical trials based on administration of adult stem cells from bone marrow or non bone marrow origins have been mixed, likely due to the low engraftment and limited differentiation of the injected cells. In this work, we analyzed the regenerative potential of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (hSSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. Injection of only 10000 hSSEA-1+ cells in ischemic hind limb of Nude mice was enough to enhanced by 56%, 41%, 74% and 26% the ischemic to non-ischemic angiographic score, paw perfusion, capillary and arteriolar densities respectively when compared to administration of PBS or 10000 murine embryonic feeder cells (p<0.001, n=10). Of interest, at this dose, administration of human bone marrow-derived cells or human cord blood-derived endothelial progenitor cells was inefficient whereas that of SSEA-1- cells decreased by around 15% post-ischemic vessel growth when compared with PBS (p<0.05, n=10). SSEA-1+ cells are able to generate smooth muscle or endothelial progenitors when they are treated, for one week, with PDGF-BB or VEGF-A, respectively. Injection of 10000 PDGF-BB-treated hSSEA-1+ cells, or 10000 VEGF-A-treated hSSEA-1+ cells or 5000 of both type of cells, increased by more than 50% the revascularization process. Immunohistochemistry and FACS analysis revealed the presence and localization of SSEA-1+ in ischemic tissue around vascular structures and their differentiation into cells with endothelial phenotype. Finally, transfection with siRNA directed against the endonuclease Dicer abrogated the pro-angiogenic and pro-vasculogenic capacities of SSEA-1+ and, restored that of SSEA-1-, highlighting a dual role of microRNAs in reprogramming stem cells and in the control of their regenerative potential. This study unravels, for the first time, the unchallenged capacity of human multipotent cardiovascular SSEA-1+ progenitors to promote therapeutic revascularization in ischemic tissues.
- © 2012 by American Heart Association, Inc.