CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation

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 fac tors 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 loss of BM stromal cells was more severe in CXCR4‐deficient mice compared to WT mice. In addition, tra nsplantation 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 th e 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 ...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Tissue ‐Specific Stem Cells Source Type: research