Adenoviral Mediated Delivery of OSKM Factors Induces Partial Reprogramming of Mouse Cardiac Cells In Vivo

The induction ofin vivo reprogramming toward pluripotency has been demonstrated in several tissues utilizing either transgenic inducible mice or gene delivery approaches. However, the effects ofexogenous reprogramming factor expression in the mammalian heart have not been previously reported. The present study aims to investigate the response ofcardiac cells to ectopic Oct3/4, Sox2, Klf4,and cMyc (OSKM) expression in vivo using a non-integrating adenoviral vector. Direct intramyocardial injection ofthis vector achieves effective and transient OSKM overexpression in the healthy heart and after myocardial infarction. The expression ofthese factors induces transient upregulation ofa number ofendogenous pluripotency (endo-Oct3/4, Gdf3) and reprogramming related (Cdh1, Fut4) genes, confirming the induction ofcell reprogramming. Despite the initiation ofreprogramming, markers offully de-differentiated cells including Nanog remain silenced, consistent with a partially reprogrammed state. Furthermore, no indications oftumorigenesis or teratoma formation are observed. Overall, these data suggest that adenoviral mediated OSKM delivery can be utilized to induce partial in vivo reprogramming. However, the absence ofany clear regenerative effects after myocardial infarction indicates that further optimization ofvector mediated reprogramming strategies is essential to overcome barriers to therapeutic efficacy.