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J. Dev. Biol. 2016, 4(4), 32; doi:10.3390/jdb4040032

Asxl2−/− Mice Exhibit De Novo Cardiomyocyte Production during Adulthood

1
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
2
PTM Biolabs Inc., Chicago, IL 60612, USA
3
The School of Molecular and Cellular Biology, University of Illinois Urbana-Champaign, Champaign, IL 61801, USA
4
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
5
Physician Assistant Studies, Grand Valley State University, Grand Rapids, MI 49503, USA
6
Congressionally Directed Medical Research Programs, Frederick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Simon J. Conway
Received: 31 August 2016 / Revised: 26 October 2016 / Accepted: 27 October 2016 / Published: 3 November 2016
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Abstract

Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2−/− heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin+ non-cardiomyocytes in Asxl2−/− over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the Asxl2−/− heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2−/− hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2−/− heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity. View Full-Text
Keywords: heart; cardiogenic; cardiomyocyte; proliferation; regeneration; chromatin factor; epigenetic heart; cardiogenic; cardiomyocyte; proliferation; regeneration; chromatin factor; epigenetic
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MDPI and ACS Style

Brunner, R.; Lai, H.-L.; Deliu, Z.; Melman, E.; Geenen, D.L.; Wang, Q.T. Asxl2−/− Mice Exhibit De Novo Cardiomyocyte Production during Adulthood. J. Dev. Biol. 2016, 4, 32.

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J. Dev. Biol. EISSN 2221-3759 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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