Andy Chan, Joachim Greiner, Lisa Marschhäuser, Tomás A. Brennan, Stefanie Perez‐Feliz, Ankit Agrawal, Helene Hemmer, Katrin Sinning, Jennifer Wing Lam Cheung, Zafar Iqbal, Alexander Klesen, Tamara Vico, Julieta Aprea, Ingo Hilgendorf, Thomas Seidel, Martin Vaeth, Eva A. Rog‐Zielinska, Peter Köhl, Franziska Schneider‐Warme, Dominic Grün
Abstract The heart is one of the least regenerative organs in humans, and ischemic heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes that occur during cardiac wound healing is an essential prerequisite to reducing health burden and improving cardiac function after myocardial tissue damage. Here, by integrating single-cell RNA sequencing with high-resolution spatial transcriptomics, we reconstruct the spatiotemporal dynamics of the fibrotic niches after cardiac injury in adult mice. We reveal a complex multicellular network that regulates cardiac repair, including fibroblast proliferation silencing by Trem2 high macrophages to prevent excessive fibrosis. We further discovered a rare population of progenitor-like cardiomyocytes after lesion, promoted by myeloid and lymphoid niche signals. 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 atlas provides valuable insights into the heterocellular interactions that control cardiac repair.