Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle

Area of Science:

• Stem cell biology
• Cellular metabolism
• Organ regeneration

Background:

• Stem cells reside in specialized niches essential for their function.
• Hair follicle stem cells (HFSCs) differentiate into outer root sheath (ORS) cells upon activation.
• The mechanisms underlying the reversibility of ORS cells returning to a stem cell state are not fully understood.

Purpose of the Study:

• To investigate the metabolic requirements for hair follicle stem cell (HFSC) fate reversibility.
• To elucidate the role of the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis in HFSC niche regulation and fate.
• To understand the implications of metabolic control in stem cell niches for organ homeostasis.

Main Methods:

• Analysis of metabolic shifts during HFSC lineage progression.
• Investigating the role of mTORC2-Akt signaling in HFSC fate and niche maintenance.
• Utilizing genetic deletion of mTORC2 to assess its impact on hair follicle regeneration.

Main Results:

• Suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism is required for ORS cells to regain stem cell state.
• The mTORC2-Akt signaling axis within the niche regulates HFSC fate reversibility and glutamine metabolism.
• Deletion of mTORC2 impairs the re-establishment of the HFSC niche, leading to defective hair follicle regeneration and compromised HFSC maintenance.

Conclusions:

• Spatiotemporal control of stem cell metabolic states is critical for maintaining organ homeostasis.
• The mTORC2-Akt pathway plays a vital role in regulating stem cell fate reversibility and hair follicle regeneration.
• Metabolic regulation is a key factor in the long-term maintenance and function of hair follicle stem cells.