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.

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信号中感知需求，然后转变为具有生物能量活性的后代以区分和满足这些细胞需求，这一点至关重要。然而，这些造血早期步骤的需求适应调节回路在很大程度上是未知的。在这里，我们表明溶酶体，复杂的营养传感和信号中心，受到转录因子 EB (TFEB) 和 MYC 的二分调控，以平衡激活 LT-HSC 和指导其谱系命运所需的分解代谢和合成代谢过程。TFEB 介导的内溶酶体途径诱导导致膜受体降解，限制 LT-HSC 代谢和有丝分裂激活，促进静止和自我更新，并控制红细胞 - 骨髓的承诺。相比之下，MYC 参与生物合成过程，同时抑制溶酶体分解代谢，驱动 LT-HSC 活化。我们的研究将 TFEB 介导的溶酶体活性控制确定为适当和协调的干细胞命运确定的中央调节中心。