BMP-AKT-GSK3β Signaling Restores Hair Follicle Stem Cells Decrease Associated with Loss of Sfrp1

Area of Science:

• Stem cell biology
• Dermatology
• Molecular signaling

Background:

• Wnt signaling is crucial for hair follicle stem cell (HFSC) regulation.
• Secreted frizzled-related protein 1 (Sfrp1), a Wnt antagonist, is present in HFSCs, but its function is unclear.

Purpose of the Study:

• To investigate the role of Sfrp1 in regulating HFSCs and the hair follicle cycle.
• To elucidate the molecular mechanisms underlying Sfrp1's function in HFSC maintenance.

Main Methods:

• Analysis of Sfrp1 knockout (Sfrp1-/-) and heterozygous (Sfrp1+/-) mice.
• Assessment of HFSC markers (Lgr5, Axin2) and proliferation.
• Investigation of the BMP-AKT-GSK3β signaling pathway.
• In vitro studies using cultured keratinocytes.

Main Results:

• Sfrp1 loss led to HFSC depletion, increased proliferation, and accelerated hair follicle cycling.
• HFSC markers Lgr5 and Axin2 were reduced in Sfrp1+/- and Sfrp1-/- mice.
• Sfrp1-/- mice showed HFSC restoration by the second telogen, unlike Sfrp1+/- mice.
• Restoration in Sfrp1-/- mice was linked to β-catenin downregulation via BMP-AKT-GSK3β signaling.
• Sfrp1 loss in keratinocytes enhanced proliferation, reversible with BMPR1A or GSK3β inhibitors.

Conclusions:

• Sfrp1 plays a critical role in maintaining the HFSC pool and regulating the hair follicle cycle.
• A novel cross-talk between BMP-AKT-GSK3β signaling pathways mediates Sfrp1's regulation of β-catenin activity.
• This mechanism is essential for balancing the HFSC pool and ensuring skin tissue homeostasis.