TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

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. [Display omitted] •TFEB nuclear localization and lysosomal activity decreases upon LT-HSC activation•MYC drives LT-HSC metabolic and mitogenic activation and inhibits lysosomal genes•TFEB induces lysosomal degradation of TfR1, balancing myeloid/erythroid fate choices•TFEB and lysosomal activity preserve quiescence and enhance self-renewal of LT-HSCs García-Prat et al. show that lysosomes are regulated dichotomously by TFEB and c-MYC and are crucial for regulating human LT-HSC quiescence, self-renewal, and erythroid/myeloid lineage specification. Anabolic-catabolic lysosomal activity, including endolysosomal degradation of membrane receptors such as TfR1, is required for environmental sensing and activation of LT-HSCs.