Osteopontin promotes infarct repair

Itai Rotem, Tal Konfino, Tal Caller, Yeshai Schary, Olga Shaihov-Teper, Dahlia Palevski, Nir Lewis, Daria Lendengolts, Nili Naftali-Shani, Jonathan Leor

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Understanding how macrophages promote myocardial repair can help create new therapies for infarct repair. We aimed to determine what mechanisms underlie the reparative properties of macrophages. Cytokine arrays revealed that neonatal cardiac macrophages from the injured neonatal heart secreted high amounts of osteopontin (OPN). In vitro, recombinant OPN stimulated cardiac cell outgrowth, cardiomyocyte (CM) cell-cycle re-entry, and CM migration. In addition, OPN induced nuclear translocation of the cytoplasmatic yes-associated protein 1 (YAP1) and upregulated transcriptional factors and cell-cycle genes. Significantly, by blocking the OPN receptor CD44, we eliminated the effects of OPN on CMs. OPN also activated the proliferation and migration of non-CM cells: endothelial cells and cardiac mesenchymal stromal cells in vitro. Notably, the significant role of OPN in myocardial healing was demonstrated by impaired healing in OPN-deficient neonatal hearts. Finally, in the adult mice, a single injection of OPN into the border of the ischemic zone induced CM cell-cycle re-entry, improved scar formation, local and global cardiac function, and LV remodelling 30 days after MI. In summary, we have shown, for the first time, that recombinant OPN activates cell-cycle re-entry in CMs. In addition, recombinant OPN stimulates multiple cardiac cells and improves scar formation, LV remodelling, and regional and global function after MI. Therefore, we propose OPN as a new cell-free therapy to optimize infarct repair.

Original languageEnglish
Article number51
JournalBasic Research in Cardiology
Volume117
Issue number1
DOIs
StatePublished - Dec 2022

Funding

FundersFunder number
Seymour Fefer Foundation
Israel Science Foundation
Sackler Faculty of Medicine, Tel-Aviv University

    Keywords

    • Cardiomyocyte
    • Cell cycle
    • Macrophage
    • Myocardial infarction
    • Osteopontin

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