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

• Published in: Science signaling Vol. 17; no. 860; p. eadl5100
• Main Authors: Rondeau, Vincent, Kalogeraki, Maria, Roland, Lilian, Nader, Zeina Abou, Gourhand, Vanessa, Bonaud, Amélie, Lemos, Julia, Khamyath, Mélanie, Moulin, Clémentine, Schell, Bérénice, Delord, Marc, Bidaut, Ghislain, Lecourt, Séverine, Freitas, Christelle, Anginot, Adrienne, Mazure, Nathalie, McDermott, David H, Parietti, Véronique, Setterblad, Niclas, Dulphy, Nicolas, Bachelerie, Françoise, Aurrand-Lions, Michel, Stockholm, Daniel, Lobry, Camille, Murphy, Philip M, Espéli, Marion, Mancini, Stéphane J C, Balabanian, Karl
• Format: Journal Article
• Language: English
• Published: United States 29.10.2024
• Subjects: Animals; Cell Differentiation; Gene Knock-In Techniques; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Mutation; Oxidative Phosphorylation; Primary Immunodeficiency Diseases - genetics; Primary Immunodeficiency Diseases - metabolism; Primary Immunodeficiency Diseases - pathology; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Warts
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.adl5100

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 mutation ( ) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in 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.