TY - JOUR
T1 - Inducible cardiomyocyte injury within the atrioventricular conduction system uncovers latent regenerative capacity in mice
AU - Wang, Lin
AU - Bhakta, Minoti
AU - Fernandez-Perez, Antonio
AU - Munshi, Nikhil V.
N1 - Funding Information:
We thank the UT Southwestern Medical Center Histology Core Facility for technical expertise, Jose Cabrera for graphical assistance, Cheryl Nolen for mouse colony maintenance, Colby Ayers for statistical advice, Hesham Sadek, Eric Olson, and Ning Liu for critical review of the manuscript, and members of the Munshi laboratory for scientific discussions. We also thank Ari Bennett and Gabriela Orquera-Tornakian for key contributions during the revision process. This work was supported by the NIH (HL136604, HL133642, and HL135217, to NVM), the Burroughs Wellcome Fund (1009838, to NVM), and the March of Dimes Foundation (5-FY13-203, to NVM).
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021
Y1 - 2021
N2 - The cardiac conduction system (CCS) ensures regular contractile function, and injury to any of its components can cause cardiac dysrhythmia. Although all cardiomyocytes (CMs) originate from common progenitors, the CCS is composed of biologically distinct cell types with unique functional and developmental characteristics. In contrast to ventricular cardiomyocytes, which continue to proliferate after birth, most CCS cells terminally exit the cell cycle during fetal development. Although the CCS should thus provide a poor substrate for postnatal injury repair, its regenerative capacity remains untested. Here, we describe a genetic system for ablating CMs that reside within the atrioventricular conduction system (AVCS). Adult mouse AVCS ablation resulted in regenerative failure characterized by persistent atrioventricular conduction defects and contractile dysfunction. In contrast, AVCS injury in neonatal mice led to recovery in a subset of these mice, thus providing evidence for CCS plasticity. Furthermore, CM proliferation did not appear to completely account for the observed functional recovery, suggesting that mechanisms regulating recovery from dysrhythmia are likely to be distinct from cardiac regeneration associated with ventricular injury. Taken together, we anticipate that our results will motivate further mechanistic studies of CCS plasticity and enable the exploration of rhythm restoration as an alternative therapeutic strategy.
AB - The cardiac conduction system (CCS) ensures regular contractile function, and injury to any of its components can cause cardiac dysrhythmia. Although all cardiomyocytes (CMs) originate from common progenitors, the CCS is composed of biologically distinct cell types with unique functional and developmental characteristics. In contrast to ventricular cardiomyocytes, which continue to proliferate after birth, most CCS cells terminally exit the cell cycle during fetal development. Although the CCS should thus provide a poor substrate for postnatal injury repair, its regenerative capacity remains untested. Here, we describe a genetic system for ablating CMs that reside within the atrioventricular conduction system (AVCS). Adult mouse AVCS ablation resulted in regenerative failure characterized by persistent atrioventricular conduction defects and contractile dysfunction. In contrast, AVCS injury in neonatal mice led to recovery in a subset of these mice, thus providing evidence for CCS plasticity. Furthermore, CM proliferation did not appear to completely account for the observed functional recovery, suggesting that mechanisms regulating recovery from dysrhythmia are likely to be distinct from cardiac regeneration associated with ventricular injury. Taken together, we anticipate that our results will motivate further mechanistic studies of CCS plasticity and enable the exploration of rhythm restoration as an alternative therapeutic strategy.
UR - http://www.scopus.com/inward/record.url?scp=85116229411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116229411&partnerID=8YFLogxK
U2 - 10.1172/JCI138637
DO - 10.1172/JCI138637
M3 - Article
C2 - 34596051
AN - SCOPUS:85116229411
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 19
M1 - e138637
ER -