2. Academic Validation
  3. Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness

Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness

  • Blood. 2022 Jul 26;blood.2022016112. doi: 10.1182/blood.2022016112.
Changzheng Li 1,  Binghuo Wu 1,  Yishan Li 1,  Yaxi Liu 2,  Jin Wang 1,  Jiayi Xie 1,  Xi Xu 3,  Xiaobin Tian 1,  Zhitao Ye 1,  Jingjing Guan 1,  Jie Chen 1,  Siyu Xie 1,  Baolin Zhang 1,  Boyong Cai 1,  Qianhao Wang 4,  Haopeng Yu 5,  Tian Lan 6,  Cheuk Him Man 7,  Xunlei Kang 8,  Pengxu Qian 9,  John M Perry 10,  Aibin He 11,  Linjia Jiang 12,  Meng Zhao 1
Affiliations

Affiliations

  • 1 Sun Yat-sen University, Guangzhou, China.
  • 2 Peking-Tsinghua Center for Life Sciences, beijing, Delaware, China.
  • 3 Nanfang Hospital, Guangzhou, China.
  • 4 Peking-Tsinghua Center for Life Sciences, beijing, China.
  • 5 Sichuan University, sichuan, China.
  • 6 Guangdong Pharmaceutical University, guangzhou, China.
  • 7 The University of Hong Kong, Hong Kong, Hong Kong.
  • 8 University of Missouri, columbia, Missouri, United States.
  • 9 Zhejiang University, Hangzhou, China.
  • 10 Children's Mercy Kansas City, Kansas City, Missouri, United States.
  • 11 Peking University, beijing, China.
  • 12 Sun Yat-sen Memorial Hospital, Guangzhou, China.
PMID: 35881840 DOI: 10.1182/blood.2022016112
Abstract

Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal, with limited progress. Here, we show that Enzyme sphingosine kinase 2 (SphK2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of SphK2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, SphK2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, SphK2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the SphK2 catalytic activity. Deletion of SphK2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial Oxidative Phosphorylation and generation of Reactive Oxygen Species. Overall, targeting SphK2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.

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