Details

Autor(en) / Beteiligte

• García-Prat, Laura
• Kaufmann, Kerstin B.
• Schneiter, Florin
• Voisin, Veronique
• Murison, Alex
• Chen, Jocelyn
• Chan-Seng-Yue, Michelle
• Gan, Olga I.
• McLeod, Jessica L.
• Smith, Sabrina A.
• Shoong, Michelle C.
• Parris, Darrien
• Pan, Kristele
• Zeng, Andy G.X.
• Krivdova, Gabriela
• Gupta, Kinam
• Takayanagi, Shin-Ichiro
• Wagenblast, Elvin
• Wang, Weijia
• Lupien, Mathieu
• Schroeder, Timm
• Xie, Stephanie Z.
• Dick, John E.

Titel

TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

Ist Teil von

• Cell stem cell, 2021-10, Vol.28 (10), p.1838-1850.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.