Abstract

Despite the intense research dedicated to deciphering hair follicle biology, one must acknowledge that this structure remains an enigma This brief review addresses several aspects of hair follicle biology, highlighting possible new research avenues, including glycobiology and exosome-mediated cell-to-cell interactions. Computer science, algorithms and bioinformatics are expected to advance our understanding of hair follicle biology.

Introduction

Despite more than 70 years of intense research and a vast collection of published results, it is still necessary to unravel some mysteries about the hair follicle, especially its biology, and to identify clues to better solve not only common problems such as telogen effluvium, hair thinning and whitening, but also devastating cases of alopecia, such as androgenetic alopecia, frontal fibrosing alopecia, alopecia areata, localised, totalis or universalis.

The enigma of behaviour and structure

Hair follicle behaviour is characterised by a succession of active (anagen) and dormant (telogen) phases, separated by intense tissue remodelling processes, both regression (catagen phase) and regeneration (neogen phase).A bi-stable behaviour is attributed to the follicle, as it autonomously and stochastically moves from an active steady state to a dormant stable state and vice versa.
Regarding the structure, the active anagen follicle presents more than fifteen cell types distributed in two compartments of mesenchymal origin (dermal papilla and connective tissue sheath) and four of epithelial origin (matrix, outer root sheath, inner root sheath and stem)..Despite its great complexity, the hair follicle is a fully integrated and controlled structure that maintains its homeostasis: after being dissected out of its natural environment, the hair follicle is able to produce in vitro a structurally similar fibre to in vivo scalp hair.

The enigma of hair follicle influence network

The hair follicle comes under a complex network of positive and negative influences, including growth factors, morphogenic factors, their receptors, signalling pathways, hormones and diffusible metabolites. To better understand the function of the network, local gradients, half-life, diffusion at distance, and storage and release of these various factors have to be taken into consideration.
It is the delicate balance of these opposing influences that defines the Yin-Yang of the hair follicle.

The enigma of hair shape

Hair curliness is programmed from the bulb and is linked to asymmetry in the expression of structural proteins, including K38, K82 and insulin-like growth factor binding protein 5.

GWAS

The advent of genome-wide association studies (GWAS) and next-generation sequencing brings hope for a broader knowledge about gene mutations associated with hair loss; the shape and quality of hair; and the whitening of hair strands.
Genomic studies have identified mutations directly linked to some congenital hair abnormalities, such as woolly hair syndrome, monilethrix, hypertrichosis, hypotrichosis and hair length.
Moreover, several gene loci and polymorphisms associated with androgenetic alopecia and alopecia areata have been found. It is important to consider gender effects, local epigenetic control, and examples where a given mutation is associated with different capillary phenotypes (diameter, shape, and whitening of hair).

Glycobiology

The fine-tuning of the control of hair biology and the stem cell fate depends not only on gene expression, but also on the glycans.
Glycans, besides being a source and storage of energy, have structural roles and modulate cell-to-cell signalling pathways through their interactions with receptors and ligands, such as lectins and growth factors, respectively.
The glycogen stored in the mid-outer root sheath is especially important as a source of energy, and supposedly plays a key role in the aerobic glycolysis process, which is required for matrix cell proliferation and hair growth maintenance.

Lipids

Lipids have been identified in the human hair cuticle, cortex and medulla and are structural components of the hair follicle.
Ceramides and 18-methyleicosanoic acid (18-MEA) are known for their structural role in the hair fibre cuticle and the progressive disappearance of these lipids along the hair fibre is related to the age of the cuticle layers.
Other lipids play regulatory roles. Steroids, including androgens and oestrogens; receptor ligands activated by peroxisome proliferators (PPAR); vitamin D and retinoic acid have been reported to modulate hair growth.
The hair follicle presents a full metabolic pathway of prostaglandins, from arachidonic acid, in a complex network of receptors. It has been suggested that PGE2, PGF2α and their analogues favour hair growth maintenance, while PGD2 is an inhibitor of hair growth and triggers the anagen-to-catagen transition.
The importance of lipids in the communication between molecular networks is yet to be established.

Exosomes

As the hair follicle is compartmentalised, exosomes are expected to be important for transmitting elements capable of modulating intercellular communication. Recently it has been discovered that exosomes play a role in Wnt secretion and transport, as well as mediating at distance interactions between keratinocytes, melanocytes and fibroblasts.
The structure and molecular content of exosomes certainly merit further study in the hair follicle context.

Conclusion and outlook

By observing the pathways that have been identified for controlling follicular morphogenesis, hair growth and hair loss, hair fibre pigmentation and its autonomous and stochastic behaviour, it is concluded that the hair follicle concentrates physiological processes that tightly control homeostasis, that is, it encompasses most of the rules that govern tissue organisation.
Therefore, expanding our knowledge of hair biology and bioinformatics should be encouraged since it will likely be of great help in the integration  of functional, spatial and temporal data, as well as in the development of an integrative view of the functioning of the hair follicle and its pathological conditions.

Reference

Bernard BA. The hair follicle enigma. Exp Dermatol. 2017;26:472-7.