YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division.

Area of Science:

• Cell Biology
• Mammalian Physiology
• Signaling Pathways

Background:

• Adult mammalian cells, like cardiomyocytes, typically exist in a quiescent, cell cycle-arrested state.
• The mechanisms maintaining this quiescence in vivo are poorly understood, with most knowledge derived from cell culture.
• Cardiomyocytes exit the cell cycle postnatally and remain arrested throughout life.

Purpose of the Study:

• To investigate the cell cycle kinetics of adult cardiomyocytes induced to re-enter the cell cycle.
• To elucidate the molecular and mechanical barriers to cardiomyocyte division in vivo.
• To understand how YAP5SA (an active form of YAP) influences cardiomyocyte cell cycle progression.

Main Methods:

• Clonal analyses were used to track YAP5SA-induced cardiomyocyte division.
• Single-cell RNA sequencing and marker gene analysis provided molecular insights.
• Functional studies examined the roles of sarcomere disassembly and P21 in cell cycle progression.

Main Results:

• YAP5SA expression enabled efficient cardiomyocyte division, with over 20% of clones showing increased cell numbers.
• Cardiomyocytes re-entered the cell cycle at G1/S, with S phase lasting approximately 48 hours.
• Sarcomere disassembly was necessary for progression to mitosis, but G2/M phase progression was inefficient, partly due to P21-mediated checkpoint activity.

Conclusions:

• YAP5SA can overcome the myocardial microenvironment's constraints to promote cardiomyocyte division.
• Inhibiting P21 function improves G2/M progression, highlighting checkpoint activity as a key barrier.
• This research provides novel insights into the in vivo mechanisms governing cell cycle quiescence in adult mammals.