Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism

Yukai Lu; Zihao Zhang; Song Wang; Yan Qi; Fang Chen; Yang Xu; Mingqiang Shen; Mo Chen; Naicheng Chen; Lijing Yang; Shilei Chen; Fengchao Wang; Yongping Su; Mengjia Hu; Junping Wang

doi:10.1016/j.stemcr.2022.01.011

Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism

Stem Cell Reports. 2022 Mar 8;17(3):599-615. doi: 10.1016/j.stemcr.2022.01.011. Epub 2022 Feb 10.

Authors

Yukai Lu¹, Zihao Zhang¹, Song Wang¹, Yan Qi¹, Fang Chen¹, Yang Xu¹, Mingqiang Shen¹, Mo Chen¹, Naicheng Chen¹, Lijing Yang¹, Shilei Chen¹, Fengchao Wang¹, Yongping Su¹, Mengjia Hu², Junping Wang³

Affiliations

¹ State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, China.
² State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, China; Chinese PLA Center for Disease Control and Prevention, No. 20 Dongda Street, Fengtai District, Beijing 100071, China. Electronic address: [email protected].
³ State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, China. Electronic address: [email protected].

Abstract

Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c^-/-) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.

Keywords: Srebf1c; TSC1; hematopoietic stem cell; mTOR; mitochondrial metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Division
Hematopoietic Stem Cells* / metabolism
Mammals / metabolism
Mice
Mitochondria / metabolism
Sirolimus / pharmacology
Sterol Regulatory Element Binding Protein 1
TOR Serine-Threonine Kinases* / metabolism

Substances

Srebf1 protein, mouse
Sterol Regulatory Element Binding Protein 1
TOR Serine-Threonine Kinases
Sirolimus