Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization

Zhang, Jing and Muri, Jonathan and Fitzgerald, Gillian and Gorski, Tatiane and Gianni-Barrera, Roberto and Masschelein, Evi and D'Hulst, Gommaar and Gilardoni, Paola and Turiel, Guillermo and Fan, Zheng and Wang, TongTong and Planque, Mélanie and Carmeliet, Peter and Pellerin, Luc and Wolfrum, Christian and Fendt, Sarah-Maria and Banfi, Andrea and Stockmann, Christian and Soro-Arnáiz, Inés and Kopf, Manfred and De Bock, Katrien. (2020) Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization. Cell metabolism, 31 (6). pp. 1136-1153.e7.

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Official URL: https://edoc.unibas.ch/79021/

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Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cell and Gene Therapy (Banfi)
UniBasel Contributors:Banfi, Andrea
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:02 Nov 2020 10:44
Deposited On:02 Nov 2020 10:44

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