Abstract 16925: In Vivo Crosstalk Between Transplanted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Host Myocardial Cells
Objectives: Induced pluripotent stem cell (iPSC) and their derivatives are attractive candidates for therapeutic use, with the potential to replace deficient cells and to improve functional recovery in injury or disease settings. Here we test the hypothesis that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) can engraft after transplantation into mouse myocardial tissue and are able to secrete cytokines as a molecular mechanism to attenuate cardiac remodeling after ischemia.
Methods and Results: iPSCs were generated from human fibroblasts and successfully differentiated in vitro using a small molecule-based protocol. Immunohistochemistry, quantitative PCR, FACS, and electrophysiological measurements confirmed successful differentiation into an almost pure population of immature CMs (>90% troponin+). To demonstrate therapeutic potential, 2x106 iPSC-CMs stably expressing firefly luciferase and GFP were transplanted into adult female NOD/SCID mice with LAD-induced myocardial infarction (N=15/group). Transplanted cells revealed limited engraftment beyond 28 days in the ischemic myocardium as assessed by longitudinal bioluminescent imaging. Animals transplanted with iPSC-CMs showed significant functional improvement and attenuated cardiac remodeling compared to PBS-treated control animals as assessed by MRI (LVEF: iPSC-CMs 25.5±1.9% vs. control 14.5±1.3%, N=8/group, P<0.05). Furthermore, single cell profiling of transplanted iPSC-CMs showed increased expression of pro-angiogenic and anti-apoptotic cytokines under ischemic conditions. Importantly, laser capture microdissection (LCM) also showed corresponding increase in several pro-angiogenic genes (VEGFA, ANG1, FGF2 and SDF-1α) from the surrounding host myocardial cells (N=4-6/group, P<0.05). Taken together, these data demonstrate that the iPSC-CMs were capable of releasing growth factors in the ischemic environment which was associated with increased neovascularization.
Conclusions: Transplantation of human iPSC-CMs into ischemic mouse myocardium can attenuate cardiac remodeling and improve LV function. Because of limited engraftment, most of the positive effects are possibly explained by paracrine activation of the cells.
- © 2013 by American Heart Association, Inc.