Autocrine/paracrine CXCL12/CXCR4-CXCR7 signaling within the bone marrow osteo-vascular niche: impact on lymphoid specification and commitment of hematopoietic stem cells – OSTEOVALYMPH

Hematopoietic stem and progenitor cells are responsible for replenishing immune cells and reside in bone marrow (BM) endosteal and vascular niches. The divergence of lymphoid and myeloid lineages occurs at the multipotent progenitor (MPP) stage. Although numerous studies focus on molecular regulation of MPP lineage specification, the influence of extracellular factors or localization of MPPs in distinct niches remain to be explored. Distinct subpopulations of lineage-biased MPPs operate together to control blood leukocyte production. Both the localization and niches of these MPP subsets in BM are unknown. It is also unclear whether regional BM localization of MPP subpopulations impacts their lineage specification and commitment through specific adhesion cues or chemokine signaling. Reciprocally, it is unknown whether MPPs can regulate their own niche through interactions with BM stroma, and if so, by which mechanisms. The general objective of this project that gathers three partners with complementary expertise in osteo-immunology, hematology and leuko-stroma interaction biology aims at delineating how CXCL12 and its two receptors, namely CXCR4 and CXCR7/ACKR3, contribute to the integrity and maintenance of the BM osteo-vascular niches. We will also determine whether the CXCL12/CXCR4-CXCR7 trio endows these niche elements with the capacity to support MPP localization and differentiation during hematopoiesis in mice and humans. Reciprocally, we will ask whether MPPs use this axis to influence their niches. The global strategy will consist in characterizing the functional expression of the CXCL12/CXCR4-CXCR7 trio in MPP subsets as well as in the osteo-vascular niche elements. Microarray-based trans-interactome analyses of these cell populations will be used to identify and validate ligand/receptor pairs involved in MPP/stroma crosstalks that govern MPP positioning and specification. This will be addressed in the context of gain-of-CXCR4-function mutation found in WHIM Syndrome (WS), which has been reproduced in mouse model and that causes defects in MPPs and deregulated expression of CXCL12 in BM. Access to BM and blood samples from healthy and WS subjects to translate results to human is an asset for the project.