Division of Hematology/Oncology, Tisch Cancer Institute.
Department of Neurology, and.
Blood Adv. 2018 Oct 23;2(20):2766-2779. doi: 10.1182/bloodadvances.2018024273.
The limited number of hematopoietic stem cells (HSCs) in umbilical cord blood (UCB) units restricts their use for stem cell transplantation. Ex vivo treatment of UCB-CD34 cells with valproic acid (VPA) increases the number of transplantable HSCs. In this study, we demonstrate that HSC expansion is not merely a result of proliferation of the existing stem cells but, rather, a result of a rapid reprogramming of CD34CD90 cells into CD34CD90 cells, which is accompanied by limited numbers of cell divisions. Beyond this phenotypic switch, the treated cells acquire and retain a transcriptomic and mitochondrial profile, reminiscent of primary HSCs. Single and bulk RNA-seq revealed a signature highly enriched for transcripts characteristic of primary HSCs. The acquisition of this HSC signature is linked to mitochondrial remodeling accompanied by a reduced activity and enhanced glycolytic potential. These events act in concert with a modest upregulation of p53 activity to limit the levels of reactive oxygen species (ROS). Inhibition of either glycolysis or p53 activity impairs HSC expansion. This study indicates that a complex interplay of events is required for effective ex vivo expansion of UCB-HSCs.
脐血（UCB）单位中造血干细胞（HSCs）的数量有限，限制了它们在干细胞移植中的应用。用丙戊酸（VPA）体外处理 UCB-CD34 细胞可增加可移植 HSCs 的数量。在这项研究中，我们证明 HSC 的扩增不仅仅是现有干细胞增殖的结果，而是 CD34CD90 细胞迅速重编程为 CD34CD90 细胞的结果，伴随着有限数量的细胞分裂。在这种表型转换之外，经过处理的细胞获得并保留了类似于原代 HSCs 的转录组和线粒体特征。单细胞和批量 RNA-seq 揭示了一个特征，该特征高度富集了原代 HSCs 特征的转录本。获得这种 HSC 特征与线粒体重塑有关，伴随着活性降低和糖酵解潜力增强。这些事件与 p53 活性的适度上调协同作用，以限制活性氧（ROS）的水平。抑制糖酵解或 p53 活性会损害 HSC 的扩增。这项研究表明，需要一系列复杂的事件相互作用才能有效地对 UCB-HSCs 进行体外扩增。
