TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate.
Cell Stem Cell
; 28(10): 1838-1850.e10, 2021 10 07.
Article
em En
| MEDLINE
| ID: mdl-34343492
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.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Hematopoese
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article