Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization
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. Mehr anzeigen
Persistenter Link
https://doi.org/10.3929/ethz-b-000417556Publikationsstatus
publishedExterne Links
Zeitschrift / Serie
Cell MetabolismBand
Seiten / Artikelnummer
Verlag
Cell PressOrganisationseinheit
09560 - De Bock, Katrien / De Bock, Katrien
03596 - Kopf, Manfred / Kopf, Manfred
03819 - Wolfrum, Christian / Wolfrum, Christian
03819 - Wolfrum, Christian / Wolfrum, Christian
Förderung
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