RNA next-generation sequencing of cardiac fibroblasts isolated from young and old mice 7 days post-MI

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. The use of young animal models fails to mirror the clinical scenario of aged human patients, as aging is associated to less well-defined cellular identities that can alter the overall picture of cardiac repair. Here, we explore the active role of cardiac fibroblasts in post-MI ventricular remodeling, aiming to identify fibroblast-specific pathways through the lens of aging that enhance translational relevance. Cardiac fibroblasts were isolated from mice with MI through 5 day-culture of total interstitial population of cardiac cells under fibroblast-favoring conditions. The expression profiling of these cells was conducted as the initial approach to depict fibroblasts-specific changes that are common to young and old animals. For a translational perspective of the study, a group of young animals that endured MSC therapy after MI surgery was also included, to help identify the molecular changes that are amenable for therapeutic modulation. This analysis revealed GLIPR1 as being activated in cardiac fibroblasts within the infarct zone during the maturation phase post-MI, thus suggesting a role in the fibrotic process. Further investigations indicated that the inflammatory environment post-MI induced the upregulation of GLIPR1 in the myofibroblast subpopulation of infarcted cardiac fibroblasts, which promoted matrix reorganization by increase in TIMP3 expression. Our study shows a key role of GLIPR1 in modulating the matrix remodeling during cardiac repair post-MI. The data presented here provide a fundamental cellular and molecular knowledge that paves the way for further exploration of GLIPR1 as a potential therapeutic target to reduce cardiac fibrosis.