Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
Department of Regenerative Medicine Medical University of Warsaw, Warsaw, Poland.
Leukemia. 2022 Jan;36(1):248-256. doi: 10.1038/s41375-021-01352-9. Epub 2021 Jul 20.
Recent evidence indicates that extracellular adenosine triphosphate (eATP), as a major mediator of purinergic signaling, plays an important role in regulating the mobilization and homing of hematopoietic stem progenitor cells (HSPCs). In our previous work we demonstrated that eATP activates the P2X7 ion channel receptor in HSPCs and that its deficiency impairs stem cell trafficking. To learn more about the role of the P2X purinergic receptor family in hematopoiesis, we phenotyped murine and human HSPCs with respect to the seven P2X receptors and observed that, these cells also highly express P2X4 receptors, which shows ~50% sequence similarity to P2X7 subtypes, but that P2X4 cells are more sensitive to eATP and signal much more rapidly. Using the selective P2X4 receptor antagonist PSB12054 as well as P2X4-KO mice, we found that the P2X4 receptor, similar to P2X7 receptor, promotes trafficking of HSPCs in that its deficiency leads to impaired chemotaxis of HSPCs in response to a stromal-derived factor 1 (SDF-1) gradient, less effective pharmacological mobilization, and defective homing and engraftment of HSPCs after transplantation into myeloablated hosts. This correlated with a decrease in SDF-1 expression in the BM microenvironment. Overall, our results confirm the proposed cooperative dependence of both receptors in response to eATP signaling. In G-CSF-induced mobilization, a lack of one receptor is not compensated by the presence of the other one, which supports their mutual dependence in regulating HSPC trafficking.
最近的证据表明，细胞外三磷酸腺苷（eATP）作为嘌呤能信号的主要介质，在调节造血干细胞祖细胞（HSPC）的动员和归巢中起着重要作用。在我们之前的工作中，我们证明了 eATP 激活 HSPC 中的 P2X7 离子通道受体，其缺乏会损害干细胞的迁移。为了更深入地了解 P2X 嘌呤能受体家族在造血中的作用，我们对小鼠和人类 HSPC 进行了表型分析，研究了七个 P2X 受体，观察到这些细胞还高度表达 P2X4 受体，它与 P2X7 亚型有~50%的序列相似性，但 P2X4 细胞对 eATP 更敏感，信号传递得更快。使用选择性 P2X4 受体拮抗剂 PSB12054 以及 P2X4-KO 小鼠，我们发现 P2X4 受体与 P2X7 受体相似，促进 HSPC 的迁移，其缺乏会导致 HSPC 对基质衍生因子 1（SDF-1）梯度的趋化性受损、更有效的药物动员，以及移植到骨髓清除宿主后 HSPC 的归巢和植入受损。这与 BM 微环境中 SDF-1 表达的减少有关。总的来说，我们的结果证实了这两个受体在响应 eATP 信号时的协同依赖性。在 G-CSF 诱导的动员中，一种受体的缺失不能被另一种受体的存在所补偿，这支持了它们在调节 HSPC 迁移中的相互依赖性。
