Title

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

Document Type

Article

Publication Date

10-13-2022

Identifier

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 the enzyme Sphk2 (sphingosine kinase 2), 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.

Journal Title

Blood

Volume

140

Issue

15

First Page

1686

Last Page

1701

MeSH Keywords

Glycolysis; Hematopoietic Stem Cells; Phosphotransferases (Alcohol Group Acceptor); Prolyl Hydroxylases; Reactive Oxygen Species; Sphingosine

Keywords

Glycolysis; Hematopoietic Stem Cells; Phosphotransferases (Alcohol Group Acceptor); Prolyl Hydroxylases; Reactive Oxygen Species; Sphingosine

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