Hematopoietic stem cell 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 GPRASP proteins 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) post-transplant. 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 post-transplant. 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.

中文翻译：

---

GPRASP 蛋白是造血干细胞移植的关键负调节因子


造血干细胞移植（HSCT）通常用于治疗血液疾病。供体 HSC 必须在重建生态位的受损环境中生存、增殖和分化。阐明调节移植 HSC 活性的分子机制将为改善 HSCT 的努力提供信息。在这里，我们报道 GPRASP 蛋白作为 HSCT 的负调节因子。 Gprasp1 或 Gprasp2 的沉默增加了移植后造血干细胞和祖细胞 (HSPC) 的存活、静止、迁移、生态位保留和造血再生活性。我们进一步表明，GPRASP1 和 GPRASP2 促进 CXCR4 的降解，CXCR4 是移植过程中 HSC 功能的主要调节因子。 CXCR4 在 Gprasp 缺陷的 HSPC 中积累，增强其移植后的功能。因此，GPRASP 负向调节 HSC 中 CXCR4 的稳定性。我们的工作揭示了 GPRASP 蛋白是 HSCT 和 CXCR4 活性的负调节因子。未来可以利用 GPRASP/CXCR4 相互作用的破坏来提高 HSCT 的效率。