TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000510219Publication status
publishedExternal links
Journal / series
Cell Stem CellVolume
Pages / Article No.
Publisher
Cell PressSubject
Lysosomes; endocytosis; TFEB; MYC; long-term HSC; self-renewal; erythropoiesis; myelopoiesis; TfR1; anabolismOrganisational unit
03992 - Schroeder, Timm / Schroeder, Timm
Funding
179490 - Molecular dynamics in hematopoietic stem and progenitor cell fate control (SNF)
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