TY - JOUR
T1 - A novel cardiomyogenic role for Isl1+ neural crest cells in the inflow tract
AU - Hatzistergos, Konstantinos E.
AU - Durante, Michael A.
AU - Valasaki, Krystalenia
AU - Wanschel, Amarylis C.B.A.
AU - William Harbour, J.
AU - Hare, Joshua M.
N1 - Funding Information:
We thank S. M. Evans from the Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA, USA and C. Cai from the Icahn School of Medicine at Mount Sinai, NY, USA for providing the Isl1-nLacZ mice. We thank S. Wu from Stanford University School of Medicine for critically reviewing our manuscript. We thank the MMRRC for the cryopreserved Mef2c-AHF-Cre material. We also thank the ENCODE Consortium and the ENCODE production laboratory of B. Ren at UCSD for generating the ChIP-seq datasets. We acknowledge the support of the Biostatistics and Bioinformatics and Oncogenomics Shared Resources at the Sylvester Comprehensive Cancer Center and the Center for Computational Science High Performance Computing Group at the University of Miami. This work was supported by the NIH grants R01 HL107110, R01 HL094849, R01 HL110737, R01 HL084275, and 5UM HL113460; grants from the Starr Foundation; and the Soffer Family Foundation (all awarded to J.M.H.). This work was further supported by R01 CA125970 (to J.W.H.), a University of Miami Medical Scientist Training Program (to M.A.D.), the Sheila and David Fuente Graduate Program in Cancer Biology (to M.A.D.), a Center for Computational Science Fellowship (to M.A.D.), and a gift from M. J. Daily (to J.W.H.). The Sylvester Comprehensive Cancer Center also received funding from the National Cancer Institute Core Support grant P30 CA240139. The Bascom Palmer Eye Institute also received funding from NIH Core Grant P30EY014801 and a Research to Prevent Blindness Unrestricted Grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH
Publisher Copyright:
Copyright © 2020 The Authors,
PY - 2020/12/2
Y1 - 2020/12/2
N2 - The degree to which populations of cardiac progenitors (CPCs) persist in the postnatal heart remains a controversial issue in cardiobiology. To address this question, we conducted a spatiotemporally resolved analysis of CPC deployment dynamics, tracking cells expressing the pan-CPC gene Isl1. Most CPCs undergo programmed silencing during early cardiogenesis through proteasome-mediated and PRC2 (Polycomb group repressive complex 2)–mediated Isl1 repression, selectively in the outflow tract. A notable exception is a domain of cardiac neural crest cells (CNCs) in the inflow tract. These “dorsal CNCs” are regulated through a Wnt/β-catenin/Isl1 feedback loop and generate a limited number of trabecular cardiomyocytes that undergo multiple clonal divisions during compaction, to eventually produce ~10% of the biventricular myocardium. After birth, CNCs continue to generate cardiomyocytes that, however, exhibit diminished clonal amplification dynamics. Thus, although the postnatal heart sustains cardiomyocyte-producing CNCs, their regenerative potential is likely diminished by the loss of trabeculation-like proliferative properties.
AB - The degree to which populations of cardiac progenitors (CPCs) persist in the postnatal heart remains a controversial issue in cardiobiology. To address this question, we conducted a spatiotemporally resolved analysis of CPC deployment dynamics, tracking cells expressing the pan-CPC gene Isl1. Most CPCs undergo programmed silencing during early cardiogenesis through proteasome-mediated and PRC2 (Polycomb group repressive complex 2)–mediated Isl1 repression, selectively in the outflow tract. A notable exception is a domain of cardiac neural crest cells (CNCs) in the inflow tract. These “dorsal CNCs” are regulated through a Wnt/β-catenin/Isl1 feedback loop and generate a limited number of trabecular cardiomyocytes that undergo multiple clonal divisions during compaction, to eventually produce ~10% of the biventricular myocardium. After birth, CNCs continue to generate cardiomyocytes that, however, exhibit diminished clonal amplification dynamics. Thus, although the postnatal heart sustains cardiomyocyte-producing CNCs, their regenerative potential is likely diminished by the loss of trabeculation-like proliferative properties.
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U2 - 10.1126/sciadv.aba9950
DO - 10.1126/sciadv.aba9950
M3 - Article
C2 - 33268364
AN - SCOPUS:85097125158
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 49
M1 - eaba9950
ER -