Promoting cardiomyocyte proliferation for myocardial regeneration in large mammals

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Neonatal Physiology

Background:

• Heart failure stems from cardiomyocyte loss, with limited regeneration in adult mammals.
• Mammalian cardiomyocytes typically exit the cell cycle early in life, hindering repair after myocardial infarction (MI).

Purpose of the Study:

• To review evidence of cardiomyocyte proliferation in neonatal pigs following injury.
• To explore the molecular mechanisms underlying neonatal cardiomyocyte regeneration.
• To compare regenerative processes during development versus injury response.

Main Methods:

• Analysis of cardiomyocyte single-nucleus RNA sequencing data.
• Comparison of gene expression in fetal, neonatal, and injured pig hearts.
• Examination of hearts from pigs subjected to myocardial injury or apical resection surgery at different neonatal stages.

Main Results:

• Neonatal pig hearts demonstrated complete cardiomyocyte regeneration after MI on postnatal day 1 (P1).
• Increased cell-cycle activity markers were observed in regenerating cardiomyocytes.
• Evidence of proliferation was found in uninjured neonatal hearts, post-injury hearts, and after staged injury protocols.

Conclusions:

• Neonatal pig hearts possess a remarkable capacity for cardiomyocyte regeneration, driven by proliferation.
• While cell-cycle regulators are conserved, injury-induced proliferation mechanisms may differ from developmental pathways.
• These findings highlight the potential for promoting cardiac repair in neonatal models.