The bone marrow (BM) microenvironment/niche plays a key role in regulating hematopoietic stem and progenitor cell (HSPC) activities; however, mechanisms regulating niche cell function are not well understood. In this study, we show that niche intrinsic expression of the CXCR4 chemokine receptor critically regulates HSPC maintenance during steady state, and promotes early hematopoietic regeneration after myeloablative irradiation. At steady state, chimeric mice with wild‐type (WT) HSPC and marrow stroma that lack CXCR4 show decreased HSPC quiescence, and their repopulation capacity was markedly reduced. Mesenchymal stromal cells (MSC) were significantly reduced in the BM of CXCR4 deficient mice, which was accompanied by decreased levels of the HSPC supporting factors stromal cell‐derived factor‐1 (SDF‐1) and stem cell factor (SCF). CXCR4 also plays a crucial role in survival and restoration of BM stromal cells after myeloablative irradiation, where the loss of BM stromal cells was more severe in CXCR4‐deficient mice compared to WT mice. In addition, transplantation of WT donor HSPC into CXCR4‐deficient recipient mice demonstrated reduced HSPC homing and early hematopoietic reconstitution. We found that CXCR4 signaling attenuates irradiation‐induced BM stromal cell loss by upregulating the expression of the antiapoptotic protein Survivin via the PI3K pathway. Our study suggests that SDF‐1‐CXCR4 signaling in the stromal microenvironment cells plays a crucial role in maintenance of HSPCs during homeostasis, and promotes niche regeneration and early hematopoietic reconstitution after transplantation. Modulation of CXCR4 signaling in the HSPC microenvironment could be a means to enhance hematopoietic recovery after clinical hematopoietic cell transplantation.

中文翻译：

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骨髓微环境中的 CXCR4 表达是造血干细胞和祖细胞维持以及清髓后早期造血再生所必需的

骨髓 (BM) 微环境/生态位在调节造血干细胞和祖细胞 (HSPC) 活动中起关键作用；然而，调节生态位细胞功能的机制尚不清楚。在这项研究中，我们表明 CXCR4 趋化因子受体的生态位内在表达在稳定状态下严格调节 HSPC 维持，并促进清髓性照射后的早期造血再生。在稳定状态下，具有野生型 (WT) HSPC 和缺乏 CXCR4 的骨髓基质的嵌合小鼠表现出 HSPC 静止减少，并且它们的再增殖能力显着降低。CXCR4缺陷小鼠的骨髓间充质基质细胞（MSC）显着减少，同时HSPC支持因子基质细胞衍生因子-1（SDF-1）和干细胞因子（SCF）水平降低。CXCR4 在清髓性照射后 BM 基质细胞的存活和恢复中也起着至关重要的作用，与 WT 小鼠相比，CXCR4 缺陷小鼠的 BM 基质细胞损失更为严重。此外，将 WT 供体 HSPC 移植到 CXCR4 缺陷的受体小鼠中表明 HSPC 归巢和早期造血重建减少。我们发现 CXCR4 信号通过 PI3K 通路上调抗凋亡蛋白 Survivin 的表达来减轻辐射诱导的 BM 基质细胞损失。我们的研究表明，基质微环境细胞中的 SDF-1-CXCR4 信号传导在维持 HSPC 稳态过程中起着至关重要的作用，并促进移植后的生态位再生和早期造血重建。