Multi-omic Profiling of Senescence Following Myocardial Infarction Reveals Dynamic Characteristics in Cardiac Remodeling

Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a gradual increment number of senescent cells within the ischemic heart, peaking at day 7 post- MI, in both wild-type and p16Ink4a-CreERT2-mT/mG senescence reporter mice. Lineage tracing shows that senescent cells transition to non-senescent state within 4 weeks after MI. We perform single-nucleus (sn) Multiome and fluorescence-based spatial transcriptomics analyses to profile senescent cells. We next generate a reference (query dataset) based on SPiDER- βGal/p16-EGFP positivity and map it back to the snMultiome dataset. We then deconvolute senescent cells in the integrated dataset using multiple computational algorisms. Through these approaches, we reveal that fibroblasts and its subpopulation-late myofibroblasts (MF)-constitute a major proportion of senescent cells, which functionally reduce ECM production. Importantly, ischemia-induced senescent MF show less soluble collagen production compared to TGF-β1- induced non-senescent MF in vitro. At the functional level, depletion of senescent cells in vivo augments fibrosis and worsens cardiac myopathy post-MI. Our findings highlight the transient nature of senescent cells in the heart and underscore the importance of dynamic regulation of senescent cells post-MI.