Mater Research Institute-The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Goethe University, Institute for Transfusion Medicine and Immunohematology, and German Red Cross Blood Donor Service Baden-Wuerttemberg-Hessen, Frankfurt, Germany.
Leukemia. 2022 Feb;36(2):333-347. doi: 10.1038/s41375-021-01413-z. Epub 2021 Sep 13.
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-PrkdcIl2rg/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，促炎细胞因子 Oncostatin M（OSM）是骨髓（BM）中造血干细胞（HSC）龛的重要调节因子。用粒细胞集落刺激因子（G-CSF）治疗健康的人类和小鼠会显著增加血液和 BM 中 OSM 的释放。使用缺失 OSM 受体（OSMR）基因的小鼠，我们证明 OSM 提供负反馈，作为对临床相关动员分子 G-CSF 和 CXCR4 拮抗剂的 HSPC 动员的制动。同样，注射由 OSMR 复合物细胞外结构域组成的重组 OSM 分子陷阱可增强在动员能力差的 C57BL/6 和 NOD.Cg-PrkdcIl2rg/SzJ 小鼠中的 HSC 动员。从机制上讲，OSM 通过 BM 内皮细胞和间充质细胞间接减弱 HSC 对 CXCL12 的趋化反应，并增加 HSC 归巢到 BM 信号，而 BM 内皮细胞和间充质细胞是 BM 中唯一表达 OSMR 的细胞。OSM 间接上调 BM 内皮细胞上的 E-选择素表达，从而增加 HSC 的增殖。来自 Osmr 和野生型小鼠的 HSCs 的 RNA 测序表明，在缺乏 OSM 信号的情况下，HSCs 的细胞骨架重组、能量利用和循环发生改变。因此，OSM 是 HSC 龛功能的重要调节因子，限制 HSC 的动员，抗 OSM 治疗与当前的动员方案结合可能会改善用于移植的 HSPC 动员。
