Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Paris Diderot University, Paris, France; and.
Blood. 2020 Apr 2;135(14):1111-1123. doi: 10.1182/blood.2019003435.
Hematopoietic stem cell (HSC) transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate, and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that G-protein-coupled receptor-associated sorting proteins (GPRASPs) function as negative regulators of HSCT. Silencing of Gprasp1 or Gprasp2 increased the survival, quiescence, migration, niche retention, and hematopoietic repopulating activity of hematopoietic stem and progenitor cells (HSPCs) posttransplant. We further show that GPRASP1 and GPRASP2 promote the degradation of CXCR4, a master regulator of HSC function during transplantation. CXCR4 accumulates in Gprasp-deficient HSPCs, boosting their function posttransplant. Thus, GPRASPs negatively regulate CXCR4 stability in HSCs. Our work reveals GPRASP proteins as negative regulators of HSCT and CXCR4 activity. Disruption of GPRASP/CXCR4 interactions could be exploited in the future to enhance the efficiency of HSCT.
造血干细胞（HSC）移植（HSCT）常用于治疗血液疾病。供体 HSCs 必须在受损的再构建龛位环境中存活、增殖和分化。阐明调节移植 HSCs 活性的分子机制将为提高 HSCT 效率提供信息。在这里，我们报告 G 蛋白偶联受体相关分选蛋白（GPRASPs）作为 HSCT 的负调节剂。沉默 Gprasp1 或 Gprasp2 可增加移植后造血干细胞和祖细胞（HSPCs）的存活、静止、迁移、龛位保留和造血重建活性。我们进一步表明，GPRASP1 和 GPRASP2 促进了 CXCR4 的降解，CXCR4 是移植期间 HSC 功能的主要调节因子。在 Gprasp 缺陷的 HSPCs 中，CXCR4 积累，从而增强其移植后的功能。因此，GPRASPs 负调节 HSCs 中 CXCR4 的稳定性。我们的工作揭示了 GPRASP 蛋白作为 HSCT 和 CXCR4 活性的负调节剂。破坏 GPRASP/CXCR4 相互作用可能在未来被用于提高 HSCT 的效率。
