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Adenoviral Mediated Delivery of OSKM Factors Induces Partial Reprogramming of Mouse Cardiac Cells In Vivo
Author(s) -
Kisby Thomas,
Lázaro Irene,
Fisch Sudeshna,
Cartwright Elizabeth J.,
Cossu Giulio,
Kostarelos Kostas
Publication year - 2021
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000141
Subject(s) - reprogramming , klf4 , sox2 , microbiology and biotechnology , in vivo , biology , viral vector , homeobox protein nanog , cancer research , downregulation and upregulation , cell , induced pluripotent stem cell , embryonic stem cell , gene , biochemistry , recombinant dna
The induction of in vivo reprogramming toward pluripotency has been demonstrated in several tissues utilizing either transgenic inducible mice or gene delivery approaches. However, the effects of exogenous reprogramming factor expression in the mammalian heart have not been previously reported. The present study aims to investigate the response of cardiac cells to ectopic Oct3/4 , Sox2 , Klf4 , and cMyc (OSKM) expression in vivo using a non‐integrating adenoviral vector. Direct intramyocardial injection of this vector achieves effective and transient OSKM overexpression in the healthy heart and after myocardial infarction. The expression of these factors induces transient upregulation of a number of endogenous pluripotency ( endo‐Oct3/4 , Gdf3 ) and reprogramming related ( Cdh1, Fut4 ) genes, confirming the induction of cell reprogramming. Despite the initiation of reprogramming, markers of fully de‐differentiated cells including Nanog remain silenced, consistent with a partially reprogrammed state. Furthermore, no indications of tumorigenesis 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 of any clear regenerative effects after myocardial infarction indicates that further optimization of vector mediated reprogramming strategies is essential to overcome barriers to therapeutic efficacy.