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Osteopontin promotes infarct repair

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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.

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Availability of data and material

A detailed description of the methods is provided in the Data Supplement Materials. All data that support the findings are available within the article, in the Data Supplement, or upon reasonable request from the corresponding author.

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Acknowledgements

We thank Mrs. Noam Ziv for her skillful English-language editing. We thank Prof. Eldad Tzahor for his critical comments. This work was performed in partial fulfillment of requirements for the Ph.D. degree of Itai Rotem and Tal Konfino, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Funding

We gratefully acknowledge support for this project provided by grants from the Seymour Fefer Foundation and the Israel Science Foundation (ISF). Itai Rotem was supported by a Ph.D. scholarship from Mrs. Tuna Gursoy.

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  1. Itai Rotem and Tal Konfino have equal contribution.

Authors and Affiliations

  1. Faculty of Medicine, Neufeld Cardiovascular Research Institutes, Tel Aviv University, Tel-Aviv, Israel

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

  2. Tamman Cardiovascular Research Institutes, Sheba Medical Center, 52621, Tel-Hashomer, Israel

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

  3. The Leviev Cardiovascular and Thoracic Center, Sheba Medical Center, Tel-Hashomer, Israel

    Daria Lendengolts, Nili Naftali-Shani & Jonathan Leor

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Contributions

The authors confirm contributions to the paper as follows: study conception and design: IR, TK, and JL; data collection: IR, TK, TC, YS, OS-T, NL, NN-S, DL, DP, and JL; analysis and interpretation of results: IR, TK, TC, YS, OS-T, NL, and JL; draft manuscript preparation: IR, TK, TC, YS, OS-T, NL, NN-S, DL, DP, and JL. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Jonathan Leor.

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All authors declare that they have no competing interests.

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All experimental protocols were approved by the Ethical Committees of the Sheba Medical Center.

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Rotem, I., Konfino, T., Caller, T. et al. Osteopontin promotes infarct repair. Basic Res Cardiol 117, 51 (2022). https://doi.org/10.1007/s00395-022-00957-0

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