Abstract 15112: Microfluidic Single Cell Analysis Shows Porcine Induced Pluripotent Stem Cell-Derived Endothelial Cells Improve Myocardial Function by Paracrine Activation
Background: Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large animal iPSC models.
Methods and Results: Porcine adipose stromal cells (pASCs) harvested from 5 Yucatan miniswine were reprogrammed using lentivirus carrying Oct4, Sox2, Klf4, and cMyc at a 4:2:2:1 ratio to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and in vivo angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta (pAorta-ECs). To demonstrate therapeutic potential of these cells, piPSC-ECs were transplanted into mice with myocardial infarction (n=80). Compared to control, animals transplanted with piPSC-ECs showed significant functional improvement on echocardiography (fractional shortening at week 4: 27.2±1.3% vs. 22.3±1.1%; P<0.001) and magnetic resonance imaging (ejection fraction at week 4: 45.8±1.3% vs. 42.3±0.9%; P<0.05). To elucidate the biological mechanisms resulting in functional recovery, quantitative protein assays and microfluidic single cell PCR profiling showed that piPSC-ECs released significant levels of pro-angiogenic and anti-apoptotic factors in the ischemic microenvironment that promote neovascularization and cardiomyocyte survival, respectively.
Conclusion: In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function following MI via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate clinical translation of autologous iPSC-based therapy for cardiovascular diseases in the future.
- © 2012 by American Heart Association, Inc.