1. Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization.
- Author
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Bisht K, McGirr C, Lee SY, Tseng HW, Fleming W, Alexander KA, Matsumoto T, Barbier V, Sims NA, Müller-Newen G, Winkler IG, Bonig H, and Lévesque JP
- Subjects
- Animals, Bone Marrow drug effects, Female, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Bone Marrow physiology, Granulocyte Colony-Stimulating Factor administration & dosage, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cells cytology, Oncostatin M metabolism, Stem Cell Niche
- Abstract
We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-Prkdc
scid Il2rgtm1Wjl /SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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