Advances in understanding hair regrowth

Dr. Daniel Fernandes Melo
Dermatologist, Professor of Trichology at Federal University of Rio de Janeiro (UERJ), Brazil

Commentary

This is a relevant text, full of valuable information regarding the detailed functioning of the hair follicle. This article highlights the role of the epidermis and dermis in a delicate balance of antagonistic and complementary signaling pathways that guarantee follicular homeostasis. The author of this paper reinforces the importance of glycans, an emerging topic, in this complex and dynamic metabolism, highlighting that a better understanding of these substances can be key elements to unveil new aspects of the follicle growth control.

Introduction

Hair represents a true paradigm of mesenchymal and epithelial interaction. From the most initial morphogenetic phase to the complete formation of the pilosebaceous unit, the follicular cycle is controlled by an intimate interaction between epithelial and mesenchymal components. Follicular homeostasis is therefore the result of this balance.

The hair follicle is considered a composite organ, with a concentric structure. It works through mutual regulation, originating from signals that come from the dermis and epidermis. As the activity of diffusible factors, such as growth factors and morphogens, can be modulated by glycans, their possible role in hair growth control must be considered.

The hair follicle is the only constantly cyclical organ in mammals that transits from a metabolically active phase (anagen) to a resting phase (telogen) passing briefly through a regression (catagen) and a regeneration phase (neogen). The regenerative characteristic of hair is related to the cyclic activation of steam cells.

It is believed that the epithelial and mesenchymal control oscillates and guarantees the cyclical pattern of the hair follicle phases. This transition is controlled by a complex and dynamic mechanism of activation and inhibition of substances such as diffuse morphogens, cytokines, neuropeptides, hormones, prostaglandins, and growth factors. For example, it is known that insulin-like growth factor (IGF) is required for anagen maintenance. On the other hand, fibroblast growth factor (FGF) appears to be a crucial regulator of hair length in humans, as a strong inducer of the catagen phase. Recent data suggest that a delicate balance between PGE2 / PGF2a also controls the duration of the active steady state.

An interesting fact is that the resting phase (telogen) is not as quiescent as previously thought. It is divided into two periods: refractory and permissive. In the first, the strong expression of bone morphogenetic protein (BMP) keeps the follicle in the telogen phase. In the second, the progressive increase of the BMP antagonist activates the Wnt / Fzz / bcatenin pathway and triggers the onset of the neogen phase.

Glyco-biology of the human hair follicle

In the author’s opinion the human hair follicle is under the control of multiple, intricate pathways with opposing influences. Therefore, the interdependence and complementary roles of these influences allow him to propose that the hair follicle is a true paradigm of a “Yin Yang” type.

Fig. Adapted from Bruno Bernard "Advances in understanding hair growth".

Furthermore, in addition to the influence of gene expression, there is also the role of glycans in this complex metabolism. Glycans are endowed with a great diversity that can be considered, in the author’s point of view, the third language of life, after DNA and proteins.

Glycosaminoglycans are the largest class of N-Complex type glycans. Proteoglycans have one or more glycosaminoglycan side chains attached to a core protein. Glycosaminoglycans, proteoglycans, and glycan moieties of glycoproteins have long been known to play important roles in the maintenance of protein conformation and solubility, protection against proteolytic degradation, mediation of biological activity, intracellular sorting and externalization, and embryonic development and differentiation.

Regarding the role of these glycans in the hair cycle, it is already known that growth factor activation could be regulated by proteoglycans. With respect to key regulators of hair follicle growth and cycling, syndecans modulate Wnt signaling cascades, the glycosaminoglycan chains of proteoglycans shape Hedgehog gradients and signal transduction. Its inhibition provoked an immediate transition from anagen to catagen.

Finally, extracellular sulfatases appear to be critical regulators of heparin sulfate activities. Sulf1 and Sulf2, by removing glucosamine-6S groups from specific regions of heparan sulfate chain, modulate Wnt interaction with its cognate receptor Frizzled, BMP signaling by releasing BMP antagonist Noggin, and FGF-2 ability to form the functional FGF-2-HSFGFR ternary complex65,66. Of note, TGF-ß1, by inducing Sulf1 expression, might indirectly modulate Wnt, BMP, and FGF-2 activities, which could explain its inhibitory effect on hair growth. From a clinical point of view, alterations of glycosaminoglycan degradation provoke mucopolysaccharidoses and abnormalities in hair morphology, which can be reversed by appropriate enzyme replacement therapy.

Conclusion

The hair follicle is clearly endowed with a unique behavior: a permanent dialog between opposing and complementary influences, impacting all follicle compartments. Until recently, the understanding of hair growth mainly relied on the patterns of gene expression within the different hair follicle compartments throughout the hair cycle. From now on, the finetuning of the activities of growth factors and morphogens by the modulating effects of glycans will also have to be taken into consideration.

Finally, a better understanding of scalp and hair diseases will certainly provide greater insights into this complex and immune privileged tissue that is the hair follicle.