Presentation Information
[III-TLR-5]Revisiting Neonatal Mouse Heart Regeneration Theory: ErbB2 Induction Promotes Multicellular Remodeling Without Cardiomyocyte Division
○Maretoshi Hirai, Keita Fujiwara (Department of Pharmacology, Kansai Medical School, Osaka, Japan)
Keywords:
Heart regeneration,ErbB,Hypoxia
Objective: Whether ErbB signaling truly induces cardiomyocyte (CM) proliferation remains controversial due to technical difficulties in distinguishing CMs from other cell types. In this study, we resolve this using novel gene-targeted mouse lines and single-cell multi-omics. Methods: We generated two mouse lines: one for Cre-dependent ErbB2 overexpression and another for dual-labeling cell membranes and nuclei. By crossing these with Troponin T-MerCreMer mice, we rigorously tracked CM cell cycle activity. Furthermore, we decoded cell-cell communication using single-cell (scFlex) and spatial (Xenium) transcriptomics. Results: In adults, ErbB2 induction triggered rapid CM hypertrophy, transforming CMs from rod to square shapes, and hyperfunction within one week, yet no cell cycle entry was observed. Long-term ErbB2 overexpression led to CM regression and fibrosis. In contrast, in 1-week-old neonates, ErbB2 triggered robust activation of cell cycle activity in the heart. However, contrary to previous reports, EdU uptake was strictly limited to non-CMs, while CM cell cycle activation was not observed. Mechanistically, ErbB2-overexpressing CMs exhibited enhanced fatty acid metabolism and MAPK/NFκB/STAT5 activation. This metabolic shift induced specific hypoxic signatures in spatially proximal pericytes and endothelial cells. Conclusions: ErbB2-driven cardiac "growth" is not caused by CM proliferation; instead paracrine cell cycle activation of non-CMs was observed. These findings overturn the CM regeneration dogma and propose a novel multicellular remodeling mechanism.