| Summary: | Marjorie Durand,1 Jean-Marc Collombet,1 Sophie Frasca,1 Véronique Sarilar,2 Jean-Jacques Lataillade,*,1,3 Marie-Caroline Le Bousse-Kerdilès,*,4 Xavier Holy*,21Department of Medical and Surgical Assistance to the Armed Forces, French Forces Biomedical Research Institute (IRBA), Brétigny sur Orge, Cedex 91223, France; 2Department of Platforms & Technological Research, French Armed Forces Biomedical Research Institute (IRBA), Brétigny sur Orge, Cedex, 91223, France; 3Unit for Research Development, Armed Forces Blood Transfusion Center, Clamart, Cedex 92141, France; 4INSERM UMR-S/MD1197, Hôpital Paul Brousse, Villejuif, Cedex 94807, France*These authors contributed equally to this workPurpose: Bone marrow response to an organismal stress is made by orchestrating the interplay between hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). Neither the cellular nor the molecular factors that regulate this process are fully understood, especially since this mechanism probably varies depending on the type of stress. Herein, we explored the differentiation and fate of MSCs and HSPCs in mice challenged with a hematopoietic stress or a mechanical stress applied separately or in combination.Methods: Mice were subjected to 4 days of hypobaric hypoxia (hematopoietic challenge) and/or 7 days of hindlimb suspension (stromal challenge) and then sacrificed for blood and bone collection. Using hematological measurements, colony-forming unit assays, bone histomorphometry and array-based multiplex ELISA analysis, we evaluated challenge influences on both MSC and HSPC mobilization, differentiation (osteoblasts, osteoclasts, and mature blood cells) and fateResults: We found that hypoxia leads to HSPC mobilization and that an imbalance between bone formation and bone resorption accounts for this mobilization. Whilst suspension is also associated with an imbalance between bone formation and bone resorption, it does not induce HSPC mobilization. Then, we revealed cellular interactions by combining hematopoietic and stromal challenges together in mice. We showed that the hypoxia-driven HSPC mobilization is moderated by suspension. Moreover, when applied in a hypoxic environment, suspension offsets bone imbalance. We identified stroma cell-derived factors MIP-1α, HGF and SDF-1 as potent molecular key players sustaining interactions between hindlimb suspension and hypobaric hypoxia.Conclusion: Taken together, our data highlight the benefit of combining different types of stress to better understand the interplay between MSCs and HSPCs.Keywords: hypobaric hypoxia, hindlimb suspension, mesenchymal stromal cells, hematopoietic stem and progenitor cells
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