MBNL1 Regulates Programmed Postnatal Switching Between Regenerative and Differentiated Cardiac States.

Autor:	Bailey LRJ; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Molecular and Cellular Biology (L.R.J.B.), University of Washington, Seattle.; Medical Scientist Training Program (L.R.J.B.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Bugg D; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Reichardt IM; Bioengineering (I.M.R., A.N., M.R., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Ortaç CD; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Nagle A; Bioengineering (I.M.R., A.N., M.R., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Gunaje J; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Martinson A; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Johnson R; Genome Sciences (R.J., M.J.M.), University of Washington, Seattle., MacCoss MJ; Genome Sciences (R.J., M.J.M.), University of Washington, Seattle., Sakamoto T; Cardiovascular Institute, Medicine, University of Pennsylvania, Philadelphia (T.S., D.P.K.)., Kelly DP; Cardiovascular Institute, Medicine, University of Pennsylvania, Philadelphia (T.S., D.P.K.)., Regnier M; Bioengineering (I.M.R., A.N., M.R., J.D.), University of Washington, Seattle.; Center for Translational Muscle Research (M.R., J.D.), University of Washington, Seattle.; Institute for Stem Cell and Regenerative Medicine (L.R.J.B., D.B., I.M.R., C.D.O., A.N., J.G., A.M., M.R.), University of Washington, Seattle., Davis J; Laboratory Medicine and Pathology (L.R.J.B., D.B., C.D.O., J.G., A.M., J.D.), University of Washington, Seattle.; Bioengineering (I.M.R., A.N., M.R., J.D.), University of Washington, Seattle.; Center for Translational Muscle Research (M.R., J.D.), University of Washington, Seattle.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Jun 04; Vol. 149 (23), pp. 1812-1829. Date of Electronic Publication: 2024 Mar 01.
DOI:	10.1161/CIRCULATIONAHA.123.066860
Abstrakt:	Background: Discovering determinants of cardiomyocyte maturity is critical for deeply understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration, but elucidation of endogenous developmental regulators of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. MBNL1 (muscleblind-like 1) regulates fibroblast, thymocyte, and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental time points and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro assays to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is coexpressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deficiency was insufficient to promote regeneration in the adult heart because of cell cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Targeting loss of cardiomyocyte maturity and downregulation of cell cycle inhibitors through MBNL1 deletion was not sufficient to promote adult regeneration. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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