β‐catenin signalling in dermal papilla cells leads to a hairy situation

Dermal papilla (DP) are specialised mesenchymal cells that activate the formation of new hair follicles. In this issue of The FEBS Journal, Zhang and colleagues show that enhancing the β-catenin signalling pathway in DP cells allows faster and denser hair growth, providing a potential target for hair loss treatments and for improving hair regeneration techniques. The hair follicle is one of the most complex structures in the human body. It is composed of at least 15 different cell types. And, driven by its reserve of undifferentiated stem cells, it is one of the few structures that undergo cycles of degeneration and regeneration in mammals [1]. Dermal papilla (DP) cells are specialised mesenchymal cells within the hair follicle that activate the proliferation and differentiation of follicular stem cells [2]. After the initial DP-mediated hair growth induction (i.e. anagen onset), DP cells continue to stimulate the proliferation and differentiation of cells that make up the hair shaft and the root sheath [2]. As such, DP cells not only dictate the frequency at which the hair regenerates but also its colour, shape and type [3]. In fact, reduction in the number of DP cells in mice leads to hair thinning and loss [4]. One of the key features of the cells in the hair follicle is the ability to retain their histological characteristics when cultured in vitro, allowing research into the physiology of the hair follicle to be conducted with relative ease. In an effort to find effective hair preservation treatments and to reverse age-induced hair loss, extensive research has focused on deciphering the causes of natural hair loss. Given the health (treatment of burn victims), psychological (improvement of self-esteem) and cultural implications of successful hair regenerating and care treatments, it is no surprise that the market value of the hair loss treatment industry is estimated to be $2 billion [5] with more than 500 million dollars in yearly revenues [6] in the USA alone. Reconstituting functional hair follicles from adult tissues still faces major challenges, despite the advancements in culture techniques [7]. In the case of mouse cells, exogenous expression of Wnt and Bmp proteins is necessary for DP cells to maintain inductivity, or the ability to induce growth and differentiation of follicular stem cells [8, 9]. Human DP cells lose their inductivity after multiple rounds of culturing and expansion in vitro [10]; however, murine DP cells with markedly high hair-inducing capabilities express a number of marker proteins such as CD133 which can be targeted to identify, isolate and purify the relevant DP subpopulation that retains inductivity. In this issue of The FEBS Journal, Zhang et al. [11] sought to better understand the regulatory signals that promote and maintain the inductive capacity of CD133+ DP cells. Their results show that enhancing β-catenin signalling was sufficient to induce faster clonal growth of CD133+ DP cells which, after transplantation, induced hair formation more strongly than control cells, providing genetic evidence that WNT/β-catenin signalling plays a key role in stimulating hair follicle formation and maturation. As the regeneration of hair follicle requires functional β-catenin in DP cells [12], the authors first generated transgenic mice in which a truncated β-catenin protein, lacking its N-terminal ubiquitin–proteasome targeting domain, is expressed from a doxycycline inducible promoter specifically in CD133+ DP cells. This ΔN-β-catenin protein is more stable than the wild-type protein as it can no longer be degraded by the ubiquitin–proteasome pathway. The authors next induced the anagen phase (hair follicle growth phase) in these transgenic mice and their control littermates by depilating a skin patch. After a 6-day growth phase, CD133+ DP cells were isolated from the depilated skin using anti-CD133 antibodies, purified by fluorescence-activated cell sorting and grown, first as a two-dimensional culture then encapsulated in hydrogel to mimic three-dimensional growth. CD133+ DP cells isolated from transgenic mice expressing the stabilised β-catenin protein gave rise to more (~ 2-fold) and bigger spheroids than CD133+ cells isolated from control mice after 7 and 14 days. The transgenic CD133+ DP cells also showed higher expression of multiple bona fide DP marker genes, including several belonging to the WNT/β-catenin signalling pathway, suggesting a connection between enhanced β-catenin signalling and inductive and growth-promoting abilities of CD133+ DP cells. After the 14-day culture period, control or ΔN-β-catenin-expressing CD133+ cells were released from the hydrogels and mixed in equal numbers with neonatal dermal and epidermal cells. The mixture was then grafted onto nude mice kept on a doxycycline diet to maintain the expression of ΔN-β-catenin in the newly grafted CD133+ cells. Hair shafts formed from the grafted ΔN-β-catenin-expressing CD133+ cells grew longer and denser than control CD133+ DP cells, consolidating the initial hypothesis whereby higher β-catenin levels result in stronger hair follicle inductivity of DP cells (Figure 1). Histological analysis revealed that the reconstituted skin patch grafted with ΔN-β-catenin-expressing CD133+ cells contained on average ~ 2-fold more hair follicles than the skin patch grafted with control CD133+ cells (Fig. 1). The newly formed hair follicles in the ΔN-β-catenin-expressing grafts also showed a more advanced maturation stage (Fig. 1). Under these conditions, the authors also observed increased proliferation and differentiation of hair follicle matrix and hair shaft progenitor cells, as indicated by high expression levels of cell type-specific marker genes, suggesting that the faster hair growth induced by higher β-catenin levels in CD133+ DP cells is a result of increased proliferation of matrix cells. The type of hair induced by the DP cells expressing stable β-catenin, as well as the mechanism by which CD133+ DP cells stimulate the proliferation of matrix cells, awaits further study. However, this study provides solid genetic evidence for the role of WNT/β-catenin signalling in stimulating hair follicle formation and maturation without compromising hair structure or promoting aberrant growth. It also confirms previous indications that CD133+ dermal papilla cells play a crucial role in hair inductivity in vivo and could thus be targeted for maintaining mature hair follicles and for improving in vitro and in vivo hair follicle reconstruction techniques.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.