Aberrant Wnt Signaling Induces Comedo-Like Changes in the Murine Upper Hair Follicle

Stem cell proliferation and differentiation must be carefully balanced to support tissue maintenance and growth. Defective stem cell regulation may underpin diseases in many organs, including the skin. LRIG1- expressing stem cells residing in the hair follicle junction zone (JZ) support sebaceous gland homeostasis. An emerging hypothesis from observations in both mice and human holds that imbalances in key stem cell reg-ulatory pathways such as Wnt signaling may lead to abnormal fate determination of these LRIG1 thorn ve cells. They accumulate and form cystic structures in the JZ that are similar to the comedones found in human acne. To test the possible involvement of Wnt signals in this scenario, we used the Lrig1-CreERT2 mouse line to modulate Wnt signaling in JZ stem cells. We observed that persistent activation of Wnt signaling leads to JZ cyst for-mation, with associated sebaceous gland atrophy. The cysts strongly express stem cell markers and can be partially reduced by all -trans retinoic acid treatment as well as by Hedgehog signaling inhibition. Conversely, loss of Wnt signaling leads to enlargement of JZ, infundibulum, and sebaceous glands. These data implicate abnormal Wnt signaling in the generation of mouse pathologies that resemble human acne and respond to acne treatments.

Automated summary

Balancing stem cell proliferation and differentiation is crucial for tissue maintenance and growth. Dysregulation of stem cell regulation, such as Wnt signaling, may lead to abnormal fate determination of stem cells in the hair follicle junction zone (JZ), resulting in cystic structures resembling human acne. Modulating Wnt signaling in JZ stem cells in mouse models confirmed the involvement of Wnt signaling in the formation of JZ cysts and sebaceous gland atrophy. Additionally, all-trans retinoic acid treatment and Hedgehog signaling inhibition showed promising therapeutic effects on these cysts.