β-Catenin drives distinct transcriptional networks in proliferative and nonproliferative cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Regenerative Medicine

Background:

• The adult mammalian heart has limited regenerative capacity, a major challenge in treating heart failure.
• Neonatal hearts exhibit transient regenerative potential, but the mechanisms behind this loss are unclear.
• Wnt/β-catenin signaling is implicated as a crucial pathway for cardiomyocyte proliferation and cardiac regeneration.

Purpose of the Study:

• To investigate the role of Wnt/β-catenin signaling in neonatal versus adult cardiomyocyte proliferation.
• To identify the molecular mechanisms underlying the developmental loss of cardiac regenerative capacity.
• To explore the potential functional shift of Wnt/β-catenin signaling in the adult heart.

Main Methods:

• In vivo studies in neonatal and adult mice.
• In vitro studies using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs).
• Transcriptional profiling and chromatin immunoprecipitation sequencing (ChIP-seq).

Main Results:

• Wnt/β-catenin signaling promoted cardiomyocyte proliferation in neonatal mice and hPSC-CMs.
• In adult mice, Wnt/β-catenin signaling was cardioprotective but did not induce cardiomyocyte proliferation.
• A core Wnt/β-catenin-dependent transcriptional network for proliferation was identified in neonatal cells but not reactivated in adult cells.
• Adult cardiomyocytes partially reactivated a neonatal glycolytic gene program, but β-catenin failed to engage the full proliferative network.

Conclusions:

• Wnt/β-catenin signaling potentiates cardiomyocyte proliferation during development but not in the adult heart.
• The loss of cardiac regenerative capacity involves the failure of β-catenin to re-engage a specific neonatal proliferative gene network in adults.
• β-catenin function may shift from regenerative to protective in the adult heart, influenced by cardiomyocyte metabolic status and developmental changes.