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Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

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Zahid,  Hafsa
IMPRS for Biology and Computation (Anne-Dominique Gindrat), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Börno,  Stefan       
Sequencing (Stephan Lorenz), Scientific Service (Head: Claudia Thurow), Max Planck Institute for Molecular Genetics, Max Planck Society;

Timmermann,  Bernd
Sequencing (Stephan Lorenz), Scientific Service (Head: Claudia Thurow), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Giesecke-Thiel,  Claudia       
Flow Cytometry Facility (Claudia Giesecke-Thiel), Scientific Service (Head: Claudia Thurow), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Kotsaris, G., Qazi, T. H., Bucher, C. H., Zahid, H., Pöhle-Kronawitter, S., Ugorets, V., et al. (2023). Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors. npj Regenerative Medicine, 8(1): 19. doi:10.1038/s41536-023-00291-6.


Cite as: https://hdl.handle.net/21.11116/0000-000D-2BA5-9
Abstract
Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.