Abstract 3088: Myocardial Infarction Repair With iPS Induced by Human Stemness Factors
Purpose- Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiovascular differentiation, yet their potential to contribute to adult chimeric tissue for heart repair has not been tested.
Methods- Fibroblasts were here transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC using an HIV-modified, high-efficiency vector system. Reprogrammed cells were examined for morphological changes consistent with embryonic stem cell-like phenotype using field-emission scanning electron microscopy and expression profiling of specialized biomarkers to predict acquired pluripotency as confirmed by integration into preimplantation host morula via diploid aggregation. Therapeutic repair potential was tested by direct surgical transplantation of parental fibroblasts versus bioengineered iPS into acutely infarcted myocardial tissue and monitored by echocardiography, in vivo imaging with live-cell tracking, and molecular histology.
Results- Qualified iPS were obtained with ectopic gene expression as determined by spontaneous assimilation into host morula and efficient contribution to multi-lineage differentiation in chimeric embryos that included normal heart parenchyma patterning. In the adult, controlled growth of iPS with proper engraftment required immunocompetent recipients. Within infarcted hearts, intramyocardial delivery of iPS yielded progeny without disrupting cytoarchi-tecture. In contrast to parental non-reparative fibroblasts, iPS treatment restored post-ischemic contractile performance, ventricular wall thickness and electrical stability for up to 3 months following transplantation while achieving in situ multi-lineage regeneration of cardiac, smooth muscle and endothelial tissue.
Conclusion- Fibroblasts reprogrammed by human stemness factors thus acquire the potential to repair acute myocardial infarction and maintain therapeutic benefit, establishing iPS in the treatment of heart disease.