Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal

Area of Science:

• Hematology
• Cellular Biology
• Biochemistry

Background:

• Cellular stress responses are critical for hematopoietic stem cell (HSC) fate, balancing persistence and elimination.
• The relationship between stress pathways, self-renewal, and metabolic shifts during HSC quiescence exit is not well understood.

Purpose of the Study:

• To investigate the role of sphingolipid metabolism in human HSC maintenance during quiescence exit.
• To identify molecular targets for preserving HSC function.

Main Methods:

• Analysis of the sphingolipidome across the human hematopoietic hierarchy.
• Genetic and pharmacologic inhibition of the sphingolipid enzyme DEGS1.
• Assessment of HSC immunophenotype, function, and associated stress pathways (ER stress, autophagy).

Main Results:

• Distinct sphingolipidome patterns were observed across the hematopoietic hierarchy.
• DEGS1 modulation regulated lineage differentiation.
• Inhibition of DEGS1 in HSCs during quiescence exit activated coordinated stress responses, including endoplasmic reticulum stress and autophagy.
• This inhibition maintained immunophenotypic and functional HSCs.

Conclusions:

• Sphingolipid metabolism is linked to proteostatic quality control systems and HSC self-renewal.
• DEGS1 inhibition represents a potential therapeutic strategy for maintaining HSCs.
• This study provides novel therapeutic targets for enhancing HSC-based cellular therapeutics.