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  2. Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression

Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression

  • Redox Biol. 2023 Mar 8;62:102661. doi: 10.1016/j.redox.2023.102661.
Chaonan Liu 1 Weinian Liao 1 Jun Chen 1 Kuan Yu 1 Yiding Wu 1 Shuzhen Zhang 1 Mo Chen 1 Fang Chen 1 Song Wang 1 Tianmin Cheng 1 Junping Wang 2 Changhong Du 3
Affiliations

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, Army Medical University (Third Military Medical University), 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, Army Medical University (Third Military Medical University), Chongqing, 400038, China. Electronic address: wangjunping@tmmu.edu.cn.
  • 3 State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China. Electronic address: changhongdu@tmmu.edu.cn.
Abstract

There is growing appreciation that hematopoietic alterations underpin the ubiquitous detrimental effects of metabolic disorders. The susceptibility of bone marrow (BM) hematopoiesis to perturbations of Cholesterol metabolism is well documented, while the underlying cellular and molecular mechanisms remain poorly understood. Here we reveal a distinct and heterogeneous Cholesterol metabolic signature within BM hematopoietic stem cells (HSCs). We further show that Cholesterol directly regulates maintenance and lineage differentiation of long-term HSCs (LT-HSCs), with high levels of intracellular Cholesterol favoring maintenance and myeloid bias of LT-HSCs. During irradiation-induced myelosuppression, Cholesterol also safeguards LT-HSC maintenance and myeloid regeneration. Mechanistically, we unravel that Cholesterol directly and distinctively enhances Ferroptosis resistance and boosts myeloid but dampens lymphoid lineage differentiation of LT-HSCs. Molecularly, we identify that SLC38A9-mTOR axis mediates Cholesterol sensing and signal transduction to instruct lineage differentiation of LT-HSCs as well as to dictate Ferroptosis sensitivity of LT-HSCs through orchestrating SLC7A11/GPX4 expression and ferritinophagy. Consequently, myeloid-biased HSCs are endowed with a survival advantage under both hypercholesterolemia and irradiation conditions. Importantly, a mTOR Inhibitor rapamycin and a Ferroptosis inducer imidazole ketone erastin prevent excess cholesterol-induced HSC expansion and myeloid bias. These findings unveil an unrecognized fundamental role of Cholesterol metabolism in HSC survival and fate decisions with valuable clinical implications.

Keywords

Cholesterol; Ferroptosis; Hematopoietic stem cell; Ionizing radiation; Myeloid bias; Myelosuppression.

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