Cardiomyocyte Identity Crisis Without Regenerative Re-entry: A Multi-Scale Atlas of Incomplete Dedifferentiation and Intercellular Communication Rewiring in the Infarcted Human Heart
Year: 2026
Type: preprint
Abstract: Background Adult mammalian hearts regenerate poorly after myocardial infarction (MI) because cardiomyocytes largely, though not absolutely, exit the cell cycle during postnatal maturation, yet the molecular logic connecting maturation, disease-associated dedifferentiation, and intercellular communication remains unclear. Methods Public single-cell and single-nucleus transcriptomes of developing, adult, and infarcted human and mouse hearts (55,342 cardiomyocytes) are integrated with Visium spatial transcriptomics to reconstruct a cross-species maturation trajectory, a directional ligand–receptor communication atlas, and rare-event proliferation counts with donor-aware statistics. Results MI cardiomyocytes show a partial identity erosion — a stress-associated myosin isoform switch, collapse of the ventricular identity factor IRX4, and maturation-score decline — without regenerative proliferative re-entry and without fetal transcription-factor re-activation; cycling nuclei remained exceedingly rare (<0.03%), a state corroborated by chromatin accessibility and human genetics, with only the MYC regulon passing transcriptome-wide correction. Inferred communication reorganization was confined to non-myocyte compartments and did not exceed donor-label permutation nulls; cardiomyocytes remained net receivers without gaining signalling authority. IRX4 knockdown in human iPSC-derived cardiomyocytes recapitulated this identity loss, including stress-gene induction and elevated NT-proBNP secretion, and IRX4 overexpression attenuated the adrenergic stress response in IRX4-intact cardiomyocytes (orthogonal rescue untested). Conclusions These findings support a model of state–relationship decoupling, in which an intracellular cardiomyocyte identity crisis and an intercellular niche rewiring proceed independently — a decoupling we define operationally and test with donor-level null models and equivalence bounds — and may help explain the limited success of regenerative strategies that target either layer alone. Clinical Perspective What Is New? Myocardial infarction drives human cardiomyocytes into an incomplete “identity crisis,” in which the ventricular identity factor IRX4 is lost across transcriptome, chromatin, and genetic layers without re-awakening fetal proliferative programs; cycling nuclei remained exceedingly rare (<0.03%) and the MYC proliferation–metabolism network contracted, so the injured cardiomyocyte neither preserves its mature identity nor regains the ability to divide. The reorganization of intercellular communication after infarction is executed by non-myocyte compartments — most prominently fibroblasts, epicardium, and nerves — and proceeds independently of the cardiomyocyte state change; cardiomyocytes do not become communication hubs, and the stressed cardiomyocyte’s NPPB output is directed toward endothelial NPR1 receptors that are spatially uncoupled from it. What Are the Clinical Implications? Because the intracellular identity crisis and the intercellular niche rewiring are decoupled, regenerative strategies that target only one layer — for example, forced dedifferentiation or anti-fibrotic therapy alone — may remain insufficient, and restoring cardiomyocyte identity along the IRX4 axis while re-engineering the fibro-inflammatory niche emerges as a rational two-layer therapeutic strategy to evaluate.
Authors: Shigang Qiao, Lingmei Li, Chunyan He, Wei Li
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223566712