TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

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 LupienTimm Schroeder, Stephanie Z. Xie, John E. Dick

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

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.

Original languageEnglish
Pages (from-to)1838-1850.e10
JournalCell Stem Cell
Volume28
Issue number10
DOIs
StatePublished - 7 Oct 2021
Externally publishedYes

Keywords

  • MYC
  • TFEB
  • TfR1
  • anabolism
  • endocytosis
  • erythropoiesis
  • long-term HSC
  • lysosomes
  • myelopoiesis
  • self-renewal

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