MBNL1 Regulates Programmed Postnatal Switching Between Regenerative and Differentiated Cardiac States

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Regenerative Medicine

Background:

• Discovering cardiomyocyte maturity determinants is crucial for understanding heart regeneration.
• MBNL1 regulates differentiation and proliferation in various cell types.
• Investigating MBNL1's role in maintaining mature cardiomyocyte states is essential.

Purpose of the Study:

• To examine if MBNL1 promotes and maintains mature cardiomyocyte states.
• To determine if MBNL1 antagonizes cardiomyocyte proliferation.
• To elucidate MBNL1's role in cardiac regeneration.

Main Methods:

• Utilized MBNL1 gain- and loss-of-function mouse models.
• Studied various developmental time points and surgical heart regeneration models.
• Employed multi-omics, biochemical, histological, and in vitro assays.

Main Results:

• MBNL1 overexpression led to premature cardiomyocyte maturation and dysfunction.
• MBNL1 loss increased cardiomyocyte proliferation by altering cell cycle inhibitor stability.
• MBNL1 dose modulated neonatal cardiac regeneration, arresting it with overexpression and promoting it with deletion.
• MBNL1 deficiency alone did not induce adult heart regeneration due to cell cycle checkpoints.

Conclusions:

• MBNL1 is an essential regulator of cardiomyocyte differentiation, growth transition, and regenerative potential.
• MBNL1 stabilizes adult myocyte mRNAs, controlling maturation during postnatal development and adulthood.
• Loss of cardiomyocyte maturity and cell cycle inhibitors via MBNL1 deletion was insufficient for adult regeneration.