From cancer to heart fibrosis - GLIPR1 highlights a subset of myofibroblasts responsive to mesenchymal stem cell therapy after myocardial infarction

Abstract Despite recent advances in pre-clinical research on cardiac remodeling following myocardial infarction (MI), the precise molecular pathways remain poorly understood and effective therapies for heart failure are still delayed in development. Aged animal models may more accurately reflect the clinical scenario, as aging alters the cellular identities and impedes cardiac repair. In this manuscript, we investigated the expression profile of mouse cardiac fibroblasts following myocardial infarction, using both young and aged animals to enhance the translational significance. The initial studies aimed to identify fibroblast changes common to both young and old animals. Additionally, a group of young animals that underwent mesenchymal stem cells (MSC) therapy after MI surgery was included to help identify the molecular changes amenable to therapeutic modulation. The analysis uncovered Glioma- Pathogenesis Related Protein 1 (GLIPR1) activation during the post-MI maturation phase in a subset of myofibroblasts, localized to the infarct zone in young subjects and widespread throughout the ventricle in aged animals. Further investigations indicated that the inflammatory environment post-MI induced the upregulation of GLIPR1, which in turn promoted increased TIMP3 expression. These findings provide valuable insights for future research aimed at exploring the therapeutic potential of targeting GLIPR1 to reduce cardiac fibrosis post-MI. Keywords: Aged mice; Cardiac fibroblast; GLIPR1; MSC therapy; Myocardial infarction; RNA-sequencing.