Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Ann N Y Acad Sci. 2020 Apr;1466(1):39-50. doi: 10.1111/nyas.14133. Epub 2019 Jun 14.
Understanding mechanisms that determine the behavior of human hematopoietic stem cells (HSCs) is essential for developing novel strategies to expand ex vivo the number of fully functional HSCs. In this review, we focus on the complex interplay between intrinsic mechanisms regulated by transcriptional and mitochondrial networks and extrinsic signals imposed by the bone marrow microenvironment, which in concert regulate the balance between HSC self-renewal and differentiation. Such integrated signaling mechanisms that dictate the fate of HSCs in vivo must be recapitulated ex vivo to achieve successful expansion of clinically relevant HSCs. We also highlight some of the most recent ex vivo HSC expansion strategies that have currently entered clinical development. Finally, based on the evidence reviewed here and lessons learned from ex vivo HSC expansion, we raise some critical questions regarding HSC fate and the cellular plasticity of hematopoietic cells that challenge the unidirectional model of human hematopoiesis.
了解决定人类造血干细胞（HSCs）行为的机制对于开发新的策略来体外扩增具有完全功能的 HSCs 数量至关重要。在这篇综述中，我们专注于转录和线粒体网络调节的内在机制与骨髓微环境施加的外在信号之间的复杂相互作用，这些信号共同调节 HSC 自我更新和分化之间的平衡。这种决定 HSCs 体内命运的综合信号机制必须在体外重现，才能成功扩增临床上相关的 HSCs。我们还强调了一些目前正在进入临床开发的最新的体外 HSC 扩增策略。最后，基于这里综述的证据和从体外 HSC 扩增中获得的经验教训，我们提出了一些关于 HSC 命运和造血细胞的细胞可塑性的关键问题，这些问题挑战了人类造血的单向模型。
