Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Blood. 2023 Nov 16;142(20):1708-1723. doi: 10.1182/blood.2023022147.
Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC-graft products are limited by barriers in maintaining critical self-renewal and quiescence properties. The role of sphingolipid metabolism in safeguarding these essential cellular properties has been recently recognized, but not yet widely explored. Here, we demonstrate that pharmacologic and genetic inhibition of neutral sphingomyelinase 2 (nSMase-2) leads to sustained improvements in long-term competitive transplantation efficiency after ex vivo culture. Mechanistically, nSMase-2 blockade activates a canonical integrated stress response (ISR) and promotes metabolic quiescence in human and murine HSPCs. These adaptations result in part from disruption in sphingolipid metabolism that impairs the release of nSMase-2-dependent extracellular vesicles (EVs). The aggregate findings link EV trafficking and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, transient nSMase-2 inhibition enables ex vivo graft manipulation with enhanced HSPC potency.
造血干细胞和祖细胞 (HSPC) 移植可作为许多良性和恶性血液系统疾病的治愈疗法，也是基因治疗的平台。然而，由于在维持关键自我更新和静止特性方面存在障碍，对 HSPC-移植物产品进行体外操作的需求不断增长受到限制。最近已经认识到鞘脂代谢在保护这些重要细胞特性方面的作用，但尚未得到广泛探索。在这里，我们证明了中性鞘磷脂酶 2 (nSMase-2) 的药理学和遗传学抑制可导致体外培养后长期竞争移植效率的持续提高。从机制上讲，nSMase-2 阻断激活了经典的综合应激反应 (ISR)，并促进了人类和鼠类 HSPC 的代谢静止。这些适应部分归因于破坏鞘脂代谢，从而阻碍了 nSMase-2 依赖性细胞外囊泡 (EV) 的释放。总体研究结果将 EV 运输和 ISR 联系起来，作为调节 HSPC 动态平衡和长期适应性的对偶体。在翻译水平上，瞬时 nSMase-2 抑制可实现增强 HSPC 效力的体外移植物操作。
