小柯机器人

加拿大多伦多大学John E. Dick、Stephanie Z. Xie等研究人员合作发现，TFEB介导的内吞溶酶体活动控制人类造血干细胞的命运。这一研究成果于2021年8月2日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员表示，了解人类静止的长期造血干细胞（LT-HSC）如何从日常和压力介导的线索中感知需求，然后过渡到生物能量活跃的后代，从而分化和满足这些细胞的需求，这一点至关重要。然而，这些造血早期步骤的需求适应性调节回路在很大程度上是未知的。

研究人员发现，溶酶体是复杂的营养感应和信号中心，受转录因子EB（TFEB）和MYC的双重调节，进而平衡激活LT-HSC并指导其谱系命运所需的分解代谢和合成代谢过程。TFEB介导的内吞溶酶体途径诱导导致膜受体降解，限制了LT-HSC的代谢和有丝分裂的激活，促进了静止和自我更新，并控制红细胞-髓细胞的谱系决定。相反，MYC参与生物合成过程，同时抑制溶酶体的分解，推动LT-HSC的激活。这项研究发现，TFEB介导的溶酶体活动控制是正确和协调的干细胞命运决定的核心调节枢纽。

附：英文原文

Title: TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

Author: Laura García-Prat, Kerstin B. Kaufmann, Florin Schneiter, Veronique Voisin, Alex Murison, Jocelyn Chen, Michelle Chan-Seng-Yue, Olga I. Gan, Jessica L. McLeod, Sabrina A. Smith, Michelle C. Shoong, Darrien Parris, Kristele Pan, Andy G.X. Zeng, Gabriela Krivdova, Kinam Gupta, Shin-Ichiro Takayanagi, Elvin Wagenblast, Weijia Wang, Mathieu Lupien, Timm Schroeder, Stephanie Z. Xie, John E. Dick

Issue&Volume: 2021-08-02

Abstract: It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues and then transition into bioenergetically active progeny to differentiate and meet these cellular needs. However, the demand-adapted regulatory circuits of these early steps of hematopoiesis are largely unknown. Here we show that lysosomes, sophisticated nutrient-sensing and signaling centers, are regulated dichotomously by transcription factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSCs and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, promoting quiescence and self-renewal, and governing erythroid-myeloid commitment. In contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism, driving LT-HSC activation. Our study identifies TFEB-mediated control of lysosomal activity as a central regulatory hub for proper and coordinated stem cell fate determination.

DOI: 10.1016/j.stem.2021.07.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00288-5

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