Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice

Yanpu Chen; Felipe F Lüttmann; Eric Schoger; Hans R Schöler; Laura C Zelarayán; Kee-Pyo Kim; Jody J Haigh; Johnny Kim; Thomas Braun

doi:10.1126/science.abg5159

Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice

Science. 2021 Sep 24;373(6562):1537-1540. doi: 10.1126/science.abg5159. Epub 2021 Sep 23.

Authors

Yanpu Chen¹, Felipe F Lüttmann¹, Eric Schoger^{2

3}, Hans R Schöler⁴, Laura C Zelarayán^{2

3}, Kee-Pyo Kim^{4

5}, Jody J Haigh^{6

7}, Johnny Kim^{1

8}, Thomas Braun^{1

8}

Affiliations

¹ Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
² Institute of Pharmacology and Toxicology, University Medical Center Goettingen (UMG), Göttingen, Germany.
³ German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany.
⁴ Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
⁵ Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
⁶ CancerCare Manitoba Research Institute, Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁷ VIB, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium.
⁸ German Center for Cardiovascular Research (DZHK), Partner site Rhein/Main, Bad Nauheim, Germany.

PMID: 34554778
DOI: 10.1126/science.abg5159

Abstract

Cardiomyocyte (CM) replacement is very slow in adult mammalian hearts, preventing regeneration of damaged myocardium. By contrast, fetal hearts display considerable regenerative potential owing to the presence of less mature CMs that still have the ability to proliferate. In this study, we demonstrate that heart-specific expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) induces adult CMs to dedifferentiate, conferring regenerative capacity to adult hearts. Transient, CM-specific expression of OSKM extends the regenerative window for postnatal mouse hearts and induces a gene expression program in adult CMs that resembles that of fetal CMs. Extended expression of OSKM in CMs leads to cellular reprogramming and heart tumor formation. Short-term OSKM expression before and during myocardial infarction ameliorates myocardial damage and improves cardiac function, demonstrating that temporally controlled dedifferentiation and reprogramming enable cell cycle reentry of mammalian CMs and facilitate heart regeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Animals
Cell Dedifferentiation
Cell Proliferation
Cellular Reprogramming*
Doxycycline / pharmacology
Gene Expression
Heart / embryology
Heart / physiology*
Heart Neoplasms / pathology
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Mice
Mitosis
Myocardial Infarction / pathology
Myocardial Infarction / physiopathology
Myocardial Infarction / therapy
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / physiology
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Regeneration*
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism

Substances

Actins
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Myc protein, mouse
Octamer Transcription Factor-3
Pou5f1 protein, mouse
Proto-Oncogene Proteins c-myc
SOXB1 Transcription Factors
Sox2 protein, mouse
Doxycycline