He Mei, Xu Hui, Liu Guangju, Yang Ming, Zhang Wenshan, Li Yafang, Zhang Hexiao, Wang Chaoqun, Zhang Yiran, Liu Xiaolei, Xu Shiqi, Ding Yahui, Li Yinghui, Gao Yingdai, Zhang Quan
State Key Laboratory of Experimental Hematology, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Front Pharmacol. 2022 Feb 17;13:806837. doi: 10.3389/fphar.2022.806837. eCollection 2022.
Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs . An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.
据报道，有几种方法可在临床上扩增人类造血干细胞（hHSCs）并保持其多能分化能力，但只有少数方法进入了临床试验评估阶段，这限制了基于造血干细胞的治疗方法的应用。在此，我们展示了一种苯酞衍生物，紫花前胡内酯A（LA），它可以作为一种有前景的分子来扩增功能性人类脐带血（UCB）造血干细胞。一项内部筛选从九种天然产物中鉴定出LA是hHSCs扩增的优秀候选物。此外，我们的数据表明，LA处理不仅增加了表型定义的造血干细胞数量，还增强了它们的集落形成能力。异种移植试验表明，LA处理可以维持具有多谱系分化能力的hHSCs的植入不受影响。进一步的实验表明，LA通过降低细胞内和线粒体活性氧（ROS）水平来增强hHSCs的抗氧化活性。LA的鉴定为解决UCB造血干细胞数量有限的临床问题提供了一种新策略。
