TY - JOUR
T1 - Adenoviral Mediated Delivery of OSKM Factors Induces Partial Reprogramming of Mouse Cardiac Cells In Vivo
AU - Kisby, Thomas
AU - de Lázaro, Irene
AU - Fisch, Sudeshna
AU - Cartwright, Elizabeth J.
AU - Cossu, Giulio
AU - Kostarelos, Kostas
N1 - Funding Information:
The authors would like to acknowledge Maria Stylianou (University of Manchester, UK) for assistance with histological analysis, Dr. Sarah Briston (University of Manchester, UK) for assistance with manuscript editing and Dr. Maurizio Buggio (University of Manchester, UK), Matthew Drummond (University of Manchester, UK) and Soeun Ngoy (Brigham and Women's Hospital, USA) for surgical assistance. They also acknowledge the Biological Services Facility and Genomic technologies core facility at the University of Manchester, UK and the Cardiovascular Physiology Core at Brigham and Women's Hospital, USA. This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) & Medical Research Council (MRC) Centre for Doctoral Training (CDT) in Regenerative Medicine (EP/L014904/1).
Publisher Copyright:
© 2020 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - adenovirus
KW - cardiovascular
KW - gene therapy
KW - pluripotency
KW - reprogramming
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U2 - 10.1002/adtp.202000141
DO - 10.1002/adtp.202000141
M3 - Article
AN - SCOPUS:85103745504
SN - 2366-3987
VL - 4
JO - Advanced Therapeutics
JF - Advanced Therapeutics
IS - 2
M1 - 2000141
ER -