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^scidIl2rg^tm1Wjl/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.

我们表明促炎制瘤素 M (OSM) 是骨髓 (BM) 中造血干细胞 (HSC) 生态位的重要调节剂。用粒细胞集落刺激因子 (G-CSF) 治疗健康人和小鼠可显着增加血液和 BM 中的 OSM 释放。使用 OSM 受体 (OSMR) 基因无效的小鼠，我们证明 OSM 提供负反馈，作为 HSPC 动员的制动器，以响应临床相关动员分子 G-CSF 和 CXCR4 拮抗剂。同样，注射由 OSMR 复合细胞外结构域制成的重组 OSM 分子陷阱可增强动员不良的 C57BL/6 和 NOD.Cg -Prkdc ^{scid Il2rg tm1Wjl中}的HSC 动员/SzJ 小鼠。从机制上讲，OSM 减弱 HSC 对 CXCL12 的趋化反应，并通过 BM 内皮细胞和间充质细胞间接增加 HSC 归巢至 BM 信号，这些细胞是 BM 中唯一表达 OSMR 的细胞。OSM 上调 BM 内皮细胞上的 E-选择素表达，间接增加 HSC 增殖。来自Osmr ^-/-和野生型小鼠的 HSC 的 RNA 测序表明，在壁龛中没有 OSM 信号的情况下，HSC 已经改变了细胞骨架重组、能量使用和循环。因此，OSM 是抑制 HSC 动员的 HSC 生态位功能的重要调节剂，抗 OSM 疗法与目前的动员方案相结合可能会改善 HSPC 动员以进行移植。