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 Lupien; Timm Schroeder; Stephanie Z. Xie; John E. Dick

doi:10.1016/j.stem.2021.07.003

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 journal › Article › peer-review

88 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 language	English
Pages (from-to)	1838-1850.e10
Journal	Cell Stem Cell
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.stem.2021.07.003
State	Published - 7 Oct 2021
Externally published	Yes

Keywords

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

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10.1016/j.stem.2021.07.003

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García-Prat, L., Kaufmann, K. B., Schneiter, F., Voisin, V., Murison, A., Chen, J., Chan-Seng-Yue, M., Gan, O. I., McLeod, J. L., Smith, S. A., Shoong, M. C., Parris, D., Pan, K., Zeng, A. G. X., Krivdova, G., Gupta, K., Takayanagi, S. I., Wagenblast, E., Wang, W., ... Dick, J. E. (2021). TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate. Cell Stem Cell, 28(10), 1838-1850.e10. https://doi.org/10.1016/j.stem.2021.07.003

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title = "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.",

keywords = "MYC, TFEB, TfR1, anabolism, endocytosis, erythropoiesis, long-term HSC, lysosomes, myelopoiesis, self-renewal",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = oct,

day = "7",

doi = "10.1016/j.stem.2021.07.003",

language = "English",

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García-Prat, L, Kaufmann, KB, Schneiter, F, Voisin, V, Murison, A, Chen, J, Chan-Seng-Yue, M, Gan, OI, McLeod, JL, Smith, SA, Shoong, MC, Parris, D, Pan, K, Zeng, AGX, Krivdova, G, Gupta, K, Takayanagi, SI, Wagenblast, E, Wang, W, Lupien, M, Schroeder, T, Xie, SZ & Dick, JE 2021, 'TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate', Cell Stem Cell, vol. 28, no. 10, pp. 1838-1850.e10. https://doi.org/10.1016/j.stem.2021.07.003

TY - JOUR

T1 - TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

AU - García-Prat, Laura

AU - Kaufmann, Kerstin B.

AU - Schneiter, Florin

AU - Voisin, Veronique

AU - Murison, Alex

AU - Chen, Jocelyn

AU - Chan-Seng-Yue, Michelle

AU - Gan, Olga I.

AU - McLeod, Jessica L.

AU - Smith, Sabrina A.

AU - Shoong, Michelle C.

AU - Parris, Darrien

AU - Pan, Kristele

AU - Zeng, Andy G.X.

AU - Krivdova, Gabriela

AU - Gupta, Kinam

AU - Takayanagi, Shin Ichiro

AU - Wagenblast, Elvin

AU - Wang, Weijia

AU - Lupien, Mathieu

AU - Schroeder, Timm

AU - Xie, Stephanie Z.

AU - Dick, John E.

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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.

AB - 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.

KW - MYC

KW - TFEB

KW - TfR1

KW - anabolism

KW - endocytosis

KW - erythropoiesis

KW - long-term HSC

KW - lysosomes

KW - myelopoiesis

KW - self-renewal

UR - http://www.scopus.com/inward/record.url?scp=85116668744&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2021.07.003

DO - 10.1016/j.stem.2021.07.003

M3 - Article

C2 - 34343492

AN - SCOPUS:85116668744

SN - 1934-5909

VL - 28

SP - 1838-1850.e10

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 10

ER -

TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

Abstract

Keywords

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