Commentary

This reliable study provides new data showing the contraction of the dermal sheath and its role in the hair cycle. We know that the regulation of adult stem cells by their niche is necessary for tissue homeostasis, regeneration after injury, and during aging. Normal regression of hair follicles during the hair cycle poses a particular challenge for maintaining a functional proximity of stem cells to their niche, particularly the cells of the dermal papilla.

This research used mice hair to demonstrate that the follicle dermal sheath is an active smooth muscle that drives tissue remodeling through coordinated cell contraction, enabling renewed contact between the dermal papilla and hair follicle stem cells during hair follicle regression. This biomechanism of niche relocation probably may be utilized in other stem cell niche systems.

Introduction

Tissue homeostasis requires the balance of growth by cell production and regression through cell loss. In the hair cycle, during follicle regression, the niche crosses the skin through an unknown biomechanism to reach the stem cell reservoir and trigger hair growth. This paper identifies the dermal sheath as the key driver of tissue regression and niche relocation through the smooth muscle contractile machinery that generates centripetal constriction force. When sheath contraction is inhibited, the follicle regression and niche relocation cannot happen. The authors defend that the dermal sheath is a smooth muscle that drives follicle regression for reuniting niche and stem cells to regenerate tissue structure during homeostasis.

Dermal sheath is essential for reuniting stem cells and niche

As the study aimed to verify the importance of dermal sheath (DS) for niche relocation during follicle regression, the authors first established DS-specific targeting using cartilage proteoglycan Aggrecan as a genetic driver. This indicated that the dermal sheath is required for the progression of follicle regression during catagen and for niche relocation to the stem cell reservoir in the upper follicle. Then they analyzed the stalled follicle phenotype more closely to determine the degree of catagen dysfunction in nonregressing hair follicles lacking dermal sheath. Together, the analyses showed that long, nonregressed follicles resulted from a failure of hair shaft and dermal papilla movement toward the skin surface concomitant to the absence of outer root sheath progenitor apoptosis. Therefore, the dermal sheath may exert a physical force essential for the upward travel of hair shaft and dermal papilla niche.

Dermal sheath expresses the molecular machinery of smooth muscles

To explore further if the dermal sheath expressed the contractile molecular machinery of smooth muscles to execute follicle regression and niche relocation, the authors isolated dermal sheath cells for transcriptome analysis, in comparison to dermal papilla and dermal fibroblasts. The dermal sheath signature was also enriched for genes involved in “muscle filament sliding” and “smooth muscle contraction”. Myosin was active in the entire length of dermal sheath throughout catagen, supporting the dermal sheath functional contractile activity. Finally, several smooth muscle proteins were expressed in human scalp hair follicles, suggesting conservation of smooth muscle components in the dermal sheath between mice and humans.

Dermal sheath contraction is required for follicle regression

Next, the authors explored whether dermal sheath cells might contract in a smooth muscle–like fashion. So, they tested if the DS could functionally contract and compress microdissected intact hair follicles. Their data then confirmed that this contraction is functionally required for follicle regression and dermal papilla niche relocation to the stem cells.

Visualizing regression movements by intravital imaging

By intravital two-photon microscopy of unperturbed skin in live mice, researchers investigated where the dermal sheath contracts and by which force mechanism it drives niche relocation. Their labeling setup and liveimaging time frame effectively captured the movements of key components during catagen regression and confirmed the requirement of smooth muscle contraction.

Contraction at the follicle bottleneck pulls the niche via the epithelial strand

After measuring the cross-sectional diameter of the follicle-wrapping dermal sheath cell ring at this bottleneck, researchers found a significant decrease over time coinciding with shaft upward movement These data revealed that the dermal sheath moves centripetally at the bottleneck toward the center, suggesting that it contracts to generate the constriction force necessary for pushing the hair shaft upward, which then pulls the dermal papilla by its connection to the hair shaft via the epithelial strand.

Conclusion

This article answers the question of how the niche is relocated nearly the entire length of the follicle to reach its essential stem cell–adjacent position. Through intravital imaging, contraction assays in isolated cells and intact follicles ex vivo, and in vivo inhibition of contraction, it was showed that the dermal sheath is a smooth muscle that contracts to power the key follicle regression movements during the catagen phase of the hair cycle. At the end of regression, when the hair shaft has reached its final position, forces generated by the space reduction of apoptosing cells then pull in the niche next to the stem cell reservoir before launching regrowth in the next cycle that regenerates the follicle for new hair shaft production. The authors discovered another smooth muscle function—relocating a niche to its stem cell reservoir—to add to the vast array of diverse roles of smooth muscles throughout the body. This example highlights the evolutionary advantage of repurposing preexisting functionality rather than inventing new systems in the wake of new adaptive challenges.