The Biogenesis and Growth of Human Hair

DESMOND J. TOBIN

1.1 The Hair Follicle Mini-organ

1.1.1 Introduction

As social beings we communicate significantly via our physical appearance and so together with epidermal pigmentation the hair fibre-producing mini-organ accounts for most of the variation in the phenotype of different mammals and between different human population groupings. Although commonly dismissed as being of superficial importance, the hair follicle(s) (HF) is truly one of human biology's most fascinating structures. Hair growth, one of only two uniquely mammalian traits (in addition to mammary glands), serves several important functions. These include thermal insulation, camouflage (melanin affords significant protective value, e.g. change of coat colour in the arctic fox with season), social and sexual communication (involving visual stimuli, odorant dispersal etc.), sensory perception (e.g. whiskers), and protection against trauma, noxious insults, insects, etc. These features have clearly facilitated evolutionary success in animals, but it is not immediately clear how these may have proved critical for human survival. That said, one should not diminish the role of hair in social and sexual communications among humans. Because of our relative nakedness most attention and study is focused on scalp hair that, uniquely amongst primates, can be very thick, very long and very pigmented. Conversely, its absence from the human scalp can result in significant psychological trauma, e.g. in cases of androgenetic alopecia, alopecia areata and chemotherapy-induced alopecia. Our ancient pre-occupation with hair is further heightened today as our increasing longevity inevitably fuels our desire to extend youthfulness. This increasing attention to hair-care is reflected in the unremitting growth of the hair-care market, already a multi-billion euro enterprise world-wide (Euromonitor).

Unlike most other mammals, we humans have all but lost our ability to grow hair synchronously or as a wave. Instead, our hair grows in a mosaic pattern where significant autonomy of growth and pigmentation resides in individual HF. The evolutionary selective pressure for why humans developed such a luxurious growth of pigmented scalp hair is more perplexing. One possible explanation may relate to the hair fibre as a dispersal conduit for pigment – melanin is an avid binder of a broad range of toxins and metals (for further discussion see Chapter 3 in this volume). This view, advanced by Hardy, derives from the evolution of early humans along riverbanks and seacoasts. As such, a diet rich in fish, concentrators of heavy metals, could have had significant health implications. A mechanism to quickly remove these toxic metals, thereby preventing their build-up in the body, may have been exploited by melanin's capacity to bind these compounds into a rapidly dividing tissue that ultimately keratinises to form the hair fibre. The hair bulb exhibits the body's second highest rate of proliferation (after hematopoietic tissue) and so could swiftly incorporate metals and toxins into a pigmented and cornified hair shaft, and in this way limit their access to the living tissue of the highly vascularised scalp.

1.1.2 A Unique Mammalian Epithelial-Mesenchymal-Neuroectodermal Interactive System

The HF or more accurately the 'pilo-sebaceous unit' encapsulates all the important physiological processes found in the human body, namely controlled cell growth/ death, interactions between cells of different histologic type, cell differentiation and migration, hormone responsitivity etc. Thus, the value of the HF as a model for biological scientific research goes way beyond its scope for cutaneous biology or dermatology alone. Indeed, the recent and dramatic upturn in interest in HF biology has focused principally on the pursuit of two of biology's holy grails: post-embryonic morphogenesis and control of cyclical tissue activity.

The HF mini-organ is formed from a bewilderingly complex set of interactions involving ectodermal, mesodermal and neuroectodermal components, which go to elaborate five or six concentric cylinders of at least fifteen distinct interacting cell sub-populations. These together provide a truly exceptional tissue that rivals the vertebrate limb-bud as a model for studies of the genetic regulation of development. An important consideration for the remit of this book is that the formation of the HF product, its fibre, occurs in a highly time-resolved manner and so locks in a snap-shot of the individual's physiology and chemistry at the time of the hair fibre's formation. Thus, the hair fibre does not undergo further biogenic change.

1.1.3 Comparison with Other Keratinised Skin Appendages – The Nail

Hair, scales, feathers, claws, horns and nails are all derived from skin and so all consist of keratinised modified epidermal cells. Like the hair fibre, the biological and chemical composition of the nail is not altered by changes in the blood chemistry or by exposure to toxins, chemicals etc. occurring after these structures were formed (i.e. no post-biogenic change). Therefore, both hair and nails are of major interest to toxicologists and to those interested in forensic and medico-legal investigations. The slower growth of nail (toenail, 0.05 mm per day: finger nail, 0.1 mm per day) compared with human scalp hair fibres (≈ 0.35 mm per day), and the fact that nails (especially of the foot) are not normally exposed to external contaminants, make the nail particularly useful for retrospective analysis. For a discussion of this topic, the reader is directed to an excellent clinical review by Daniel et al.

1.2 Embryology of the Hair Follicle

1.2.1 Hair Follicle Induction

Hair follicles are skin appendages that develop from the human epidermis around the end of the third gestational month. The events surrounding the early stages of HF development (Figure 1.1) are currently the topic of intense research with several excellent reviews available to the interested reader. In brief, these 'inductive' events rely on signals between specialised mesenchymal cells of the dermis that lie below the superficially-arranged epidermal cells (i.e. the epidermis), which direct specialised outcomes in these epithelial (keratinocytes) and dermal cells (fibroblasts). Dermal 'first' signals are thought to determine where along the overlying epidermis a HF is likely to be produced (so-called 'patterning' controls), while the epithelium's 'first' signal is thought to determine and direct the clustering of the dermal fibroblasts to form the hair growth 'inducer' component – the so-called follicular dermal papilla. There are also 'second' signals to induce initial downgrowth of the epidermal 'placode' via a local proliferation of the HF epithelium. From these initial HF 'commitment' events, subsequent differentiation signals determine which cells will go on to form keratinocytes of the hair fibre and follicular sheaths, and which fibroblasts form the growth-inducing follicular papilla and dermal sheaths. The 'signals' referred to above are mediated by intercellular signalling molecules secreted from specific subpopulations of skin cells and which have multiple receptors/targets to transduce their effects.

Of note here is the exquisite specificity of the signalling events occurring between different cell sub-populations. For example, recombination experiments have shown that dermis taken from one body region when combined with epidermis from another body site (even in another individual) will direct the formation of HF that are characteristic of the dermis donor site. A test of this in humans was recently carried out whereby male follicular dermal tissue taken from the scalp directed the formation of terminal hairs when recombined with female arm epidermis.

The identity of the 'first' dermal and epidermal signal(s) is currently a matter of some conjecture and several molecules have been implicated in these events. However, there is increasing evidence that these may be associated with the WNT and β-catenin signalling pathway. For example, WNT signalling molecules, fibroblast growth factors, transforming growth factor, pplatelet-derived growth factor and others are thought to lead the promotion of placode formation and early HF development and addition of some of these factors can induce the formation of HF at ectopic sites. Conversely, loss of the ability to produce these factors (e.g. via mutation) can result in defective HF development. The exotically-named secreted protein sonic hedgehog (SHH) engages in highly significant signalling events between HF epithelium and mesenchyme. These dictate whether HF development continues to completion once HF placode formation has occurred. In addition to epithelial and mesenchymal cells, the developing HF follicle also contains other cell populations, most conspicuously melanocytes that pigment the developing hair fibre. The reader is directed to Chapter 3 in this volume for a discussion on the development of the follicular pigmentary unit.

The assessment of morphologically recognisable stages of HF development has recently been revisited by Paus and colleagues and these authors have produced an elegant, user-friendly, guide to HF development using neonatal black mice as their model system. I will refer to this guide when reviewing the morphological changes associated with the differentiation/development of the HF.

1.2.2 Hair Follicle Cell Differentiation

One of the enigmas of HF development is how a relatively undifferentiated cluster of epithelial and mesenchymal cells can give rise to such a large number of distinct cell lineages with variable different differentiated products (Figure 1.2).

HF morphogenesis is morphologically appreciable (Figure 1.3) only at Stage 3 when the forerunner of a HF 'bulb' becomes evident – a process reflecting the activation/induction of multiple keratinocyte differentiation pathways that lead to considerable structural change within the tissue. At Stage 3 the developing HF appears as a 'peg' of tissue consisting of an elongated column of concentrically-layered keratinocytes. The mesenchymal component of the HF, the follicular dermal papilla, is now located within a cavity of the developing epithelium bulb. The hair peg continues to elongate into the dermis of the skin during Stage 4 and there is evidence now of the formation of the inner root sheath (IRS), as it assumes a cone-shaped structure. The follicular papilla becomes progressively more invaginated by the enlarging hair bulb.

Significant additional morphological features can be distinguished in the Stage 5 developing HF. Not only does the IRS continue to develop and extend upwards within the HF, but several epithelial prominences or bulges also appear along the external wall of the developing HF called the outer root sheath (Figures 1.1 & 1.3). One of these 'bulges' will generate the future repository of the HF stems cells (e.g. for both epithelial cells and melanocytes). Another will become a site of specialised lipid-forming epithelial cells that will form the holocrine sebaceous gland. Sebum flow from this gland will coat/lubricate the hair shaft surface. Also around this time melanocytes that have migrated from the embryonic neural crest through the dermis and subsequently to the epidermis, will now distribute within the developing HF. Some of these cells will localise to the epithelial hair bulb matrix just above the follicular dermal papilla and begin to produce the pigment melanin (Figure 1.3). The first melanin granules are evident in pre-cortical keratinocytes at this stage. However, the forming fibre must now start to pass through the HF core in order to exit the skin surface. Its passage through intact follicular epithelium is facilitated by the formation of a 'hair canal', which is constructed via focal cell death or apoptosis.

The developing HF continues to extend deeper and deeper into the skin until its proximal bulbar end is situated within the adipose-rich (i.e. fat cell) subcutis. Anatomic features characteristic of Stage 6 HF include an increasing complexity of the now multilayered IRS (Figure 1.3). Furthermore, the hair shaft can now be visualised within the hair canal and melanin granules can be seen within its cortical keratinocytes.

The final two stages of HF development are characterised by the growth of the hair shaft through the IRS and hair canal until the tip of the fibre emerges from the surface of the skin (Figures 1.1 & 1.3). In addition, the aspect of the sebaceous gland changes relative to the HF horizontal axis at this stage. Finally, the HF attains its maximal length and bulk during Stage 8 when the distal hair shaft is positioned well free of the skin surface (Figures 1.1 & 1.3).

It should be stressed that the above are purely morphological descriptions, which do not do justice to the enormous molecular complexity that underpins the regulation of cell lineage commitment or cell fate induction that ultimately yields the keratinised hair fibre. Considerable research efforts are currently underway to dissect the molecular pathways and mechanisms involved. For example, cells in the hair bulb matrix that are destined to become hair shaft cortical keratinocytes express the serrate 1 and serrate 2 proteins, the ligands of the Notch 1 receptor. These same cells also express bone morphogenic protein 4 (BMP4), while the expression of Noggin, the inhibitor of BMP4, can disrupt the differentiation of the cortical keratinocytes needed for hair shaft formation.

The anatomy of the fully developed Stage 8 HF is very similar to the anatomy of the growing/cycling anagen HF in the adult. Epithelial and mesenchymal cells of the developing HF therefore contrive to produce the mature HF via massive cell proliferation and cell differentiation. However, considerable tissue sculpting is also required to fashion this complex multilayered 3-D mini-organ. Such sculpting events also require intermittent and highly localised programmed cell death (apoptosis). Only in this way can the HF assume its full hair shaft-forming status.

Cessation of hair fibre production, i.e. hair shaft growth, during Stage 8 of HF development signals entry into the 'hair growth cycle', from which the HF usually does not escape during the life of the individual. A detailed discussion of the molecular regulation of the hair growth cycle is beyond the scope of this volume; readers interested in a full treatment of this topic are directed to a recent excellent review by Stenn and Paus.

1.3 Regulation of Hair Growth

1.3.1 The Hair Growth Cycle

1.3.1.1 Introduction

The second episode in the life of the HF, i.e. its entry into the hair growth cycle, involves a paradoxical 'phoenix from the ashes' scenario. In brief, this process begins with the precipitation of the fully-formed and hair fibre-producing HF into a regression phase characterised by massive apoptosis (the first catagen). Upon completion of this catagen phase, the HF is reduced to about 30% of its original Stage 8 tissue mass. The HF thereafter enters a period of relative rest (i.e. telogen) and remains therein until the third and final episode in the HF life history, i.e. its entry into the anagen phase of the first cycle. Thereafter the HF continues with lifelong cyclical activity (Figures 1.4 & 1.5).

This first anagen of the hair growth cycle morphologically resembles several aspects of HF development in utero, so much so that the life-long cyclical activity of HF appears to recapitulate, at least in part, several embryologic events involved in HF morphogenesis. In this way signalling pathways (see below) that were active during morphogenesis are re-used during in the hair growth cycle – again underpinned by signalling events between dermal and epithelial cells.