An efficient harvest of hematopoietic stem/progenitor cells (HSPCs) after pharmacological mobilization from the bone marrow (BM) into peripheral blood (PB) and subsequent proper homing and engraftment of these cells are crucial for clinical outcomes from hematopoietic transplants. Since extracellular adenosine triphosphate (eATP) plays an important role in both processes as an activator of sterile inflammation in the bone marrow microenvironment, we focused on the role of Pannexin-1 channel in the secretion of ATP to trigger both egress of HSPCs out of BM into PB as well as in reverse process that is their homing to BM niches after transplantation into myeloablated recipient. We employed a specific blocking peptide against Pannexin-1 channel and noticed decreased mobilization efficiency of HSPCs as well as other types of BM-residing stem cells including mesenchymal stroma cells (MSCs), endothelial progenitors (EPCs), and very small embryonic-like stem cells (VSELs). To explain better a role of Pannexin-1, we report that eATP activated Nlrp3 inflammasome in Gr-1⁺ and CD11b⁺ cells enriched for granulocytes and monocytes. This led to release of danger-associated molecular pattern molecules (DAMPs) and mitochondrial DNA (miDNA) that activate complement cascade (ComC) required for optimal egress of HSPCs from BM. On the other hand, Pannexin-1 channel blockage in transplant recipient mice leads to a defect in homing and engraftment of HSPCs. Based on this, Pannexin-1 channel as a source of eATP plays an important role in HSPCs trafficking.

从骨髓 (BM) 药物动员到外周血 (PB) 后有效收获造血干/祖细胞 (HSPC) 以及随后这些细胞的正确归巢和植入对于造血移植的临床结果至关重要。由于细胞外三磷酸腺苷 (eATP) 作为骨髓微环境中无菌炎症的激活剂在这两个过程中发挥着重要作用，因此我们重点关注 Pannexin-1 通道在 ATP 分泌中的作用，以触发 HSPC 离开 BM进入 PB 以及在移植到清髓受体后它们归巢到 BM 生态位的相反过程。我们采用了针对 Pannexin-1 通道的特异性阻断肽，并注意到 HSPC 以及其他类型的 BM 干细胞（包括间充质基质细胞 (MSC)、内皮祖细胞 (EPC) 和非常小的胚胎样干细胞）的动员效率降低细胞（VSEL）。为了更好地解释 Pannexin-1 的作用，我们报告 eATP 激活富含粒细胞和单核细胞的 Gr-1 ⁺和 CD11b ⁺细胞中的 Nlrp3 炎性体。这导致危险相关分子模式分子 (DAMP) 和线粒体 DNA (miDNA) 的释放，激活补体级联 (ComC)，这是 HSPC 从 BM 最佳流出所需的。另一方面，移植受体小鼠中 Pannexin-1 通道阻断会导致 HSPC 的归巢和植入缺陷。基于此，Pannexin-1通道作为eATP的来源在HSPC运输中发挥着重要作用。