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

• Published in: Biomedicine & pharmacotherapy Vol. 187; p. 118087
• Main Authors: Marinescu-Colan, Catalina-Iolanda, Nastase-Rusu, Evelyn-Gabriela, Neculachi, Carmen-Alexandra, Martelli, Fabio, Cherry, Laudy, Preda, Mihai Bogdan, Burlacu, Alexandrina
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2025
• Subjects: Aged mice; Animals; Cardiac fibroblast; Disease Models, Animal; Fibrosis; GLIPR1; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; MSC therapy; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - therapy; Myocardium - metabolism; Myocardium - pathology; Myofibroblasts - metabolism; Myofibroblasts - pathology; Neoplasm Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; RNA-sequencing; Myocardial infarction; RNA-sequencing; Aged mice; MSC therapy; GLIPR1; Cardiac fibroblast
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2025.118087

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. [Display omitted] •GLIPR1 is upregulated in cardiac fibroblasts within infarcted areas of murine hearts.•Aging promotes GLIPR1 widespread expression in the entire infarcted ventricle.•MSC therapy impacts the cardiac fibroblasts even at later stages of post-MI repair.•GLIPR1 is associated to matrix remodeling through a direct impact on TIMP3.•MSCs may exert therapeutic effects by suppressing GLIPR1 in myofibroblasts.