Svelare l'origine specifica cellulare di Oncostatina M (OSM) nel rilascio di cellule staminali ematopoietiche (HSPCs)

Background and aims. Here, we investigate the cell-specific origin of the cytokine Oncostatin M (OSM) and its role in the release of hematopoietic stem and progenitor cells (HSPCs) into the bloodstream. HSPCs reside in the bone marrow (BM) niches, and their release is influenced by complex interactions with the nervous system, the stromal compartment of the BM, and immune cells, including those belonging to the innate immune system. The circulating levels of HSPCs exhibit a circadian oscillation in peripheral blood. Low levels of HSPCs in the blood are caused by an impaired release from the BM compartment, a condition known as "mobilopathy." This condition leads to cardiovascular complications due to reduced vascular regeneration, as well as poor outcomes in hematopoietic stem cell transplantation (HSCT) due to apheresis failure. In diabetes, myeloid cells, particularly BM macrophages, retain HSPCs in the BM by producing Oncostatin M (OSM), a cytokine that acts as a molecular brake by stimulating the production of CXCL12 by BM stromal cells. In the present study, the main objective was to investigate the contribution of neutrophil-derived OSM in the regulation of HSPC release from BM niches into the bloodstream. Methods and results. Transgenic mice characterized by the deletion of the Osm gene (Osm-/-) exhibited persistently elevated levels of circulating HSPCs throughout the entire day/night cycle, compared to wild-type mice. Consequently, Osm-/- mice showed reduced hematopoietic progenitor activity in the BM. In parallel, Osm-/- mice maintained the circadian oscillation of aged neutrophils without affecting BM phagocytic and neutrophil clock machinery. Furthermore, neutrophils particularly if aged (CXCR4highCD62Llow), expressed more OSM compared to other BM or peripheral blood immune cells. To understand the role of neutrophil-derived OSM, we employed adoptive transfers of aged neutrophils. Intravenous transfer of wild-type neutrophils decreased circulating HSPC levels in recipient mice, demonstrating that neutrophils play a role in the retention of BM HSPCs. This effect was not abolished when we injected Osm-/- neutrophils into wild-type mice. We then injected wild-type OSM-producing neutrophils into Osm-/- mice and quantified HSPCs in the peripheral blood. The injection of wild-type neutrophils failed to reduce HSPC levels, which remained elevated compared to wild-type mice. Thus, neutrophils producing OSM were unable to lower HSPC levels in the blood, even following neutrophil activation or when multiple neutrophils injections were performed to reach detectable OSM concentrations in the BM extracellular fluid. We demonstrated that, although neutrophils express higher levels of Osm compared to other immune cells, they are not the main source of OSM in the regulation of HSPC trafficking. To verify the specific cellular origin of HSPC-regulating OSM, we selectively depleted macrophages and neutrophils in wild-type and Osm-/- mice: the inhibitory effect of OSM on HSPC traffic was primarily due to macrophages rather than neutrophils. Conclusion. The neutrophil transfer approach demonstrates that neutrophils may play a role in regulating HSPC trafficking, but this is not mediated by OSM, which appears to have distinct functions depending on the cell type and context of its production.