Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Regenerative Medicine

Background:

• Adult mammalian cardiomyocytes possess limited regenerative capacity due to restricted proliferation.
• Cardiomyocyte dedifferentiation (CMDD) precedes cell-cycle reentry and heart regeneration, representing a distinct transitional cell state.
• Understanding CMDD is critical for developing strategies to enhance cardiac repair.

Purpose of the Study:

• To identify a common molecular marker for cardiomyocyte dedifferentiation (CMDD).
• To investigate the role of identified markers in cardiomyocyte cell-cycle reentry and heart regeneration.

Main Methods:

• Utilized in vitro cultured adult mouse cardiomyocytes and in vivo AAV9-mediated delivery of reprogramming factors (Oct4, Sox2, Klf4, Myc).
• Performed RNA sequencing and integrated analysis with existing datasets to identify common molecular denominators for CMDD.
• Investigated the function of the identified marker gene in various experimental models.

Main Results:

• Identified Asparagine Synthetase (Asns) as a unique molecular marker strongly correlated with CMDD.
• Demonstrated that Asns is required for increased asparagine and altered amino acid fluxes.
• Showed that Asns deficiency impairs regeneration in neonatal myocardial infarction models and affects adult cardiomyocyte cell cycle, partly via the mTORC1 pathway.

Conclusions:

• Discovered Asns as a novel marker and essential mediator for CMDD, common across multiple models.
• Revealed an Asns/mTORC1 axis dependency for dedifferentiating cardiomyocytes.
• Highlighted the potential of Asns as a therapeutic target for heart regeneration.