TY - JOUR
T1 - Osteopontin promotes infarct repair
AU - Rotem, Itai
AU - Konfino, Tal
AU - Caller, Tal
AU - Schary, Yeshai
AU - Shaihov-Teper, Olga
AU - Palevski, Dahlia
AU - Lewis, Nir
AU - Lendengolts, Daria
AU - Naftali-Shani, Nili
AU - Leor, Jonathan
N1 - Publisher Copyright:
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Cardiomyocyte
KW - Cell cycle
KW - Macrophage
KW - Myocardial infarction
KW - Osteopontin
UR - http://www.scopus.com/inward/record.url?scp=85139889102&partnerID=8YFLogxK
U2 - 10.1007/s00395-022-00957-0
DO - 10.1007/s00395-022-00957-0
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C2 - 36239866
AN - SCOPUS:85139889102
SN - 0300-8428
VL - 117
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 1
M1 - 51
ER -