Cell migration inducing protein alleviates adverse remodeling after ischemia and reperfusion injury by controlling fibroblast activation

Abstract Aims Myocardial infarction (MI) remains one of the leading causes of mortality and morbidity worldwide. Cardiac remodeling is a key process following MI, involving changes in cellular composition and extracellular matrix (ECM) to adapt to injury. However, maladaptive remodeling can worsen cardiac function, leading to cardiac fibrosis and heart failure. In the context of MI, Cell migration inducing protein (CEMIP) has come into focus and its ability to modulate hyaluronan (HA) turnover has raised critical questions about its role in post-MI healing. Methods and results This study investigates the role of global CEMIP-deletion in a murine closed chest ischemia and reperfusion injury (I/R) model. We demonstrate that Cemip is significantly upregulated in the infarcted area of the heart peaking at 72 hours post I/R. Furthermore, global deletion of Cemip resulted in significantly impaired cardiac function post I/R accompanied by an increased scar size, cardiac collagen content and PERIOSTIN deposition. Flow cytometric analyses revealed increased cardiac fibroblast abundance driven by a decrease in apoptosis at 72 h post I/R. In contrast, cardiac fibroblast proliferation was strongly inhibited in Cemip-KO fibroblasts. Upregulation of myofibroblast-associated genes as well as morphological changes in Cemip-KO cardiac fibroblasts pointed towards a crucial role of CEMIP in controlling fibroblast to myofibroblast conversion. Single-cell RNA sequencing of infarcted hearts confirmed upregulation of pro-fibrotic genes in Cemip-KO myofibroblasts. Mechanistically, Cemip-deficiency appears to maintain TGF-β activity in cardiac fibroblasts by enhancing integrin-mediated latent TGF-β activation and constitutive SMAD3 activation. This might foster a pro-fibrotic gene expression program leading to improved fibroblast survival, aberrant activation and myofibroblast persistence post I/R. Conclusions Our data suggest that CEMIP contributes to post-infarct healing by limiting excessive activation and fibroblast to myofibroblast differentiation during scar formation. Thus, CEMIP may be considered as a novel target to prevent maladaptive cardiac fibrosis and heart failure.