CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism

细胞生物学 CXCR4型 祖细胞 造血 PI3K/AKT/mTOR通路 生物 新陈代谢 信号转导 干细胞 受体 遗传学 生物化学 趋化因子
作者
Vincent Rondeau,Maria Kalogeraki,Lilian Roland,Zeina Abou Nader,Vanessa Gourhand,Amélie Bonaud,Julia P. Lemos,Mélanie Khamyath,C. Moulin,Bérénice Schell,Marc Delord,Ghislain Bidaut,Séverine Lecourt,Christelle Freitas,Adrienne Anginot,Nathalie M. Mazure,David H. McDermott,Véronique Parietti,Niclas Setterblad,Nicolas Dulphy,Françoise Bachelerie,Michel Aurrand‐Lions,Daniel Stockholm,Camille Lobry,Philip M. Murphy,Marion Espéli,Stéphane J.C. Mancini,Karl Balabanian
出处
期刊:Science Signaling [American Association for the Advancement of Science (AAAS)]
卷期号:17 (860)
标识
DOI:10.1126/scisignal.adl5100
摘要

Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated CXCR4 mutation ( CXCR4 1013 ) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in CXCR4 1013 knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in CXCR4 1013 knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.
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