Abstract P1109: DNA Damage-free iPS-Cardiomyocytes Reduces Cardiac Fibrosis

Abstract

With the increasing potential of employing cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSC) in myocardial repair, there is a demand for a method of reducing the induction of fibrosis at the transplantation site. We hypothesized that transplantation of anti-inflammatory DNA damage-free CMs (DdF-CM) could reduce fibrosis formation at the implantation site. The transcription factor, p53, is inflammation-dependent: influencing apoptosis in inflammatory or damaged cells and promoting proliferation in normal cells. Previously, we demonstrated that the p53 activator nutlin-3a could prime hiPSC culture to contain only DdF-iPSCs by inducing apoptosis in DNA-damaged inflammatory cells and successfully differentiated them into DdF-CMs. Further investigation into these cells revealed that DdF-CMs secrete exosomes containing miR-26a. These miR-26a exosomes are up-taken by host fibroblasts, reducing collagen I secretion around the graft site and overall scar size formation post-MI. Additionally, DdF-CMs transplanted mice demonstrated improved cardiac function and cell engraftment after 4 weeks post-MI. This study illustrates that transplanting DdF-CMs into infarcted hearts improves cardiac function and reduces fibrosis formation at the implantation site.