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

Cell metabolism (2020-06-04)
Jing Zhang, Jonathan Muri, Gillian Fitzgerald, Tatiane Gorski, Roberto Gianni-Barrera, Evi Masschelein, Gommaar D'Hulst, Paola Gilardoni, Guillermo Turiel, Zheng Fan, TongTong Wang, Mélanie Planque, Peter Carmeliet, Luc Pellerin, Christian Wolfrum, Sarah-Maria Fendt, Andrea Banfi, Christian Stockmann, Inés Soro-Arnáiz, Manfred Kopf, Katrien De Bock
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

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