Abstract
Introduction: With the growing field of myocardial repair through transplantation of cardiomyocytes (CM) derived from human induced pluripotent stem cells (iPSC) calls for a method for reducing fibrotic tissue development at the site of cell transplantation. We tested the hypothesis whether transplanting CMs derived from p53 stabilized (p53S) iPSCs could reduce the recruitment of fibroblast and reduce fibrosis at the site of transplantation. Methods: Transcription factor p53 functions are inflammation dependent: inducing apoptosis in inflammatory and transformed cells while promoting cell cycle in normal cells. Utilizing this discriminating nature of p53 we selected iPSCs that express less inflammatory and more anti-inflammatory markers and differentiated them into CM. Control CM (ctrl-CM) and p53S-CMs were tested for transplantation induced fibrosis in a mice model. Results and Discussion: The inflammatory markers such as accumulation of ROS, superoxide and DNA damage were significantly lesser in p53S cells. RNA sequencing revealed that, in p53S-CMs, the anti-inflammatory and anti-fibrosis signaling pathways are upregulated compared to ctrl-CMs. Transplantation of both CMs into the myocardium of ischemia induced mice resulted in cell engraftment and fibrosis around the transplantation site. However, fibrotic area was significantly reduced in p53S-CM transplanted sites evidenced by COL1 and COL4 accumulation and Sirus red staining of fibrotic tissue. In vitro treatment of human fibroblast with p53S-CM exosomes (p53S-Exo) resulted in reduced expression of fibrotic markers than ctrl-CM exosomes (Ctrl-Exo) treatment. miRNA analysis of exosomes showed that the anti-inflammatory miRNA26a is upregulated and the inflammatory miRNA101 is downregulated in p53S-Exo. Overexpression of miRNA26a mimic in ctrl-Exo abrogated the fibrosis inducing property of ctrl-Exo. Interestingly, in migration study, fibroblasts preferentially migrated towards the ctrl-CMs. Conclusion: Our results clearly shows that anti-inflammatory cells can be isolated from a population of heterogeneous cells by activating p53. Transplanting p53S-CMs attracted reduced fibroblast to the engraft site and oppose fibrosis through exosomal expression of miRNA26a.
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