TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate

Area of Science:

• Hematopoiesis
• Stem cell biology
• Cellular metabolism

Background:

• Human quiescent long-term hematopoietic stem cells (LT-HSCs) must adapt to daily and stress cues to differentiate.
• The regulatory mechanisms governing these early hematopoietic steps are not fully understood.

Purpose of the Study:

• To elucidate the demand-adapted regulatory circuits controlling LT-HSC activation and lineage commitment.
• To investigate the roles of lysosomes, transcription factor EB (TFEB), and MYC in LT-HSC fate determination.

Main Methods:

• Investigated lysosomal regulation by TFEB and MYC in LT-HSCs.
• Analyzed the balance of catabolic and anabolic processes.
• Examined the impact on LT-HSC activation, quiescence, self-renewal, and lineage commitment.

Main Results:

• Lysosomes are dichotomously regulated by TFEB and MYC.
• TFEB induces the endolysosomal pathway, promoting quiescence and erythroid-myeloid commitment by limiting activation.
• MYC promotes biosynthetic processes and represses lysosomal catabolism, driving LT-HSC activation.

Conclusions:

• TFEB-mediated lysosomal activity is a central regulator of LT-HSC fate.
• Coordinated regulation by TFEB and MYC balances catabolic and anabolic states for proper stem cell function.
• Understanding these circuits is critical for hematopoiesis and stem cell biology.