Spatio-temporal dynamics of the fibrotic niche in murine cardiac lesion repair [spatial]

The heart is one of the least regenerative organs in humans, and heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes during cardiac wound healing is an essential prerequisite to reduce health burden and improve cardiac function after myocardial tissue damage. By integrating single-cell RNA-sequencing with imaging-based spatial transcriptomics, we reconstructed the spatiotemporal dynamics of the fibrotic niche after ventricular injury in adult mice. Our analysis revealed dynamic regulation of local cell communication niches over time. We identified interactions that regulate cardiac repair, including fibroblast proliferation silencing by Trem2high macrophages that prevents excessive fibrosis. Moreover, we discovered a rare population of dedifferentiating cardiomyocytes early post-lesioning repair, sustained by signals from myeloid and lymphoid cells. Culturing non-regenerative mouse cardiomyocytes or human heart tissue with these niche factors reactivated progenitor gene expression and cell cycle activity. In summary, this spatiotemporal cell type atlas offers valuable insights into the heterocellular interactions that control cardiac repair. Cryoablation of the left ventricle (Cryo) was used as the mouse models to introduce ventricular lesions. After recovery of animals from lesion induction, we isolate the LV. 5μm formalin-fixed paraffin-embedded tissue sections (transverse plane of the LV) were mounted on a Xenium slide within the desired imaging region.