Cardiomyocyte Identity Crisis Without Regenerative Re-entry: A Multi-Scale Atlas of Incomplete Dedifferentiation and Intercellular Communication Rewiring in the Infarcted Human Heart

In the aftermath of a myocardial infarction, adult mammalian hearts struggle to regenerate due to a phenomenon known as incomplete dedifferentiation of cardiomyocytes. These mature heart cells largely cease participating in the cell cycle during the postnatal maturation process, but the molecular mechanisms linking maturation, disease-induced dedifferentiation, and intercellular communication remain poorly understood.

To shed light on this issue, researchers have integrated public single-cell and single-nucleus transcriptomes of developing, adult, and infarcted human and mouse hearts, alongside Visium spatial transcriptomics. This approach enabled the reconstruction of a cross-species maturation trajectory, a communication atlas detailing the role of ligand-receptor interactions, and rare-event proliferation counts utilizing donor-aware statistics.

The findings reveal that myocardial infarction triggers a partial identity loss in cardiomyocytes. This is characterized by a stress-associated switch in myosin isoforms, a collapse of the ventricular identity factor IRX4, and a decline in maturation scores. Importantly, this identity erosion occurs without any regenerative proliferative re-entry or the reactivation of fetal transcription factors. The cycling nuclei, indicative of cells in the cell cycle, remain exceedingly scarce in these infarcted heart tissues.