Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Stem Cells. 2020 Jul;38(7):849-859. doi: 10.1002/stem.3174. Epub 2020 Mar 19.
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.
骨髓（BM）微环境/龛在调节造血干细胞和祖细胞（HSPC）活性方面起着关键作用；然而，调节龛细胞功能的机制尚不清楚。在这项研究中，我们表明，CXCR4 趋化因子受体在固有骨髓中的表达对于 HSPC 在稳态下的维持至关重要，并促进了骨髓清除性照射后早期造血再生。在稳态下，具有野生型（WT）HSPC 和缺乏 CXCR4 的骨髓基质的嵌合小鼠显示 HSPC 静止减少，其重建能力显著降低。CXCR4 缺陷小鼠的骨髓基质细胞（MSC）明显减少，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）的水平降低。CXCR4 还在骨髓清除性照射后 BM 基质细胞的存活和恢复中发挥关键作用，与 WT 小鼠相比，CXCR4 缺陷小鼠的 BM 基质细胞丢失更严重。此外，将 WT 供体 HSPC 移植到 CXCR4 缺陷受体小鼠中表明 HSPC 归巢和早期造血重建减少。我们发现，CXCR4 信号通过 PI3K 途径上调抗凋亡蛋白 Survivin 的表达，从而减弱照射诱导的 BM 基质细胞丢失。我们的研究表明，基质细胞中的 SDF-1-CXCR4 信号在 HSPC 稳态维持中发挥关键作用，并促进移植后龛再生和早期造血重建。调节 HSPC 微环境中的 CXCR4 信号可能是增强临床造血细胞移植后造血恢复的一种手段。
