Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency

Area of Science:

• Hematology
• Cell Biology
• Metabolism

Background:

• Hematopoietic stem cells (HSCs) must remain quiescent to maintain their potency throughout life.
• The metabolic properties of HSCs, particularly during quiescence, are not fully understood.
• Glycolysis is hypothesized to be the primary energy source for quiescent HSCs.

Purpose of the Study:

• To elucidate the metabolic characteristics distinguishing quiescent from cycling-primed HSCs.
• To investigate the role of lysosomes and glycolysis in HSC quiescence and function.
• To explore potential therapeutic strategies for enhancing HSC repopulation ability.

Main Methods:

• Single-cell RNA sequencing (RNA-seq) to analyze HSC populations.
• Measurement of mitochondrial membrane potential (MMP) to differentiate HSC states.
• In vivo manipulation of glycolysis and lysosomal activity.

Main Results:

• Mitochondrial membrane potential (MMP) effectively distinguishes quiescent from primed HSCs.
• Primed HSCs utilize glycolysis, and its inhibition enhances their repopulation capacity.
• HSC quiescence is associated with abundant, large lysosomes; inhibiting lysosomal activity enlarges lysosomes, suppresses glucose uptake, sequesters mitochondria, and dramatically boosts HSC repopulation.

Conclusions:

• Lysosomal activity is a key regulator of HSC quiescence and metabolic state.
• Restraining lysosomal activation preserves HSC quiescence and potency.
• Targeting lysosomal activity represents a potential therapeutic avenue for improving HSC function and transplantation outcomes.