Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization
Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization
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DOI：
10.1038/s41375-021-01413-z
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发表时间：
2021-09-13
期刊：
影响因子：
11.4
通讯作者：
Levesque, Jean-Pierre
中科院分区：
文献类型：
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作者：
Bisht, Kavita;McGirr, Crystal;Levesque, Jean-Pierre
我们发现，促炎性抑瘤素M（OSM）是骨髓（BM）中造血干细胞（HSC）小生境的重要调节因子。用粒细胞集落刺激因子（G-CSF）治疗健康人和小鼠显著增加血液和BM中OSM的释放。使用OSM受体（OSMR）基因缺失的小鼠，我们证明OSM提供了一种负反馈，作为对HSPC动员的制动，以响应临床相关的动员分子G-CSF和CXCR 4拮抗剂。同样，注射由OSMR复合物胞外结构域制成的重组OSM分子陷阱增强了动员不良的C57 BL/6和NOD.Cg-Prkdc（scid）Il 2 rg（tm 1 Wjl）/SzJ小鼠中的HSC动员。从机制上讲，OSM减弱HSC对CXCL 12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信号传导，BM内皮细胞和间充质细胞是BM中唯一表达OSMR的细胞。OSM上调BM内皮细胞上E-选择素的表达，间接增加HSC增殖。来自Osmr（-/-）和野生型小鼠的HSC的RNA测序表明，在壁龛中不存在OSM信号的情况下，HSC改变了细胞骨架重组、能量利用和循环。因此，OSM是抑制HSC动员的HSC生态位功能的重要调节剂，并且抗OSM治疗与当前动员方案组合可改善用于移植的HSPC动员。
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)Il2rg(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.