During myelosuppressive injury or age, hematopoietic stem cells (HSCs) have diminished abilities to adequately replace and maintain the hematopoietic system. The objective of enlarging and renewing HSCs for therapeutic purposes has been pursued for a long time and has yet to be successful. For a study, researchers sought to demonstrate that HSCs have significant levels of the enzyme Sphk2, or sphingosine kinase 2, which produces the lipid metabolite sphingosine-1-phosphate.
The ability of HSCs to regenerate themselves is significantly increased when Sphk2 is deleted. More crucially, Sphk2 deletion enhances function and maintains the multilineage potential of HSCs during aging while generally preserving the gene expression pattern seen in young HSCs. Sphk2 facilitates HIF1 ubiquitination in the nucleus through interactions with prolyl hydroxylase 2 and the Von Hippel-Lindau protein, irrespective of the enzymatic activity of Sphk2.
Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1 protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently improves the metabolic fitness of HSCs to improve anaerobic glycolysis while suppressing mitochondrial oxidative phosphorylation and the production of reactive oxygen species to increase hypoxic responses.
In general, Sphk2 inhibition was considered a potential approach to increase and reactivate functional HSCs by improving the metabolic fitness of HSCs.
