Dvt. & Physiology of the hair

Dr Mesfin Hunegnaw,

Consultant dermatologist and venerologist, AAU, Medical faculty, Dept. of Dermatovenerology

In the normal situation, every hair grows, is retained for a time without further growth, and is eventually shed and then replaced.

• While human body hair has little protective value, specialized hairs, such as eyelashes and eyebrows and hairs inside the nostrils and external ears, do afford some protection from the environment.

• Thick scalp hair provides protection from actinic damage.

• Another function of human hair is its role as a “touch organ” involved in sensory reception.

• All hair follicles have multiple sensory nerve endings that respond to pressure on the hair shaft, thereby providing nearly all of the modalities of tactile sensibility.

• Hair also acts as a conduit in the delivery of scents secreted by the sebaceous and apocrine glands.

• Animals have specialized sinus hairs in the skin of the upper & lower lips, the snout, & above the eyebrows.

• These tactile hairs (vibrissae), encircled by a blood-filled sinus and with more than 2000 sensory nerve endings, aid nocturnal animals in orientation and function as another set of “eyes.”

• Hair is important model system for studying a number of basic biologic problems, including the regulation of cell proliferation and differentiation, morphogenesis, pattern formation, and cyclical regulation.

• Many of these processes are influenced by the mesenchyme; thus the hair follicle is an ideal system for investigating mesenchymal-epithelial interactions.

• In addition to an involvement in hair and scalp disorders, the hair follicle is now considered to potentially play a role in epidermal homeostasis, wound healing, and skin tumorigenesis.

Embryology and Anatomy• In human fetuses, the first primordial hair follicles form

at approx. 9 weeks' gestation & are distributed mainly in the areas of the eyebrows, upper lip, & chin.

• The bulk of the remaining follicles begin to develop at approximately 4 to 5 months gestation in a cephalad-to-caudad direction.

• During fetal life, production of follicles occurs in several interspersed waves.

• Primary or secondary follicles are formed b\n already existing follicles as the skin expands.

• The secondary follicle develops on each side of the established follicle, producing typical groupings of three hairs.

• Under normal circumstances, new follicles can not develop in adult skin.

• Follicular morphogenesis begins with an inductive event that involves the exchange of signals between epithelial and mesenchymal cells, and proceeds through stages of;

Initiation, elongation, & cellular differentiation.

I-The first “pregerm” stage of development, A focal crowding of nuclei in the epidermal basal layer

is matched by a cluster of mesenchymal cells beneath the basement membrane.

The crowding of basal keratinocytes causes a slight “bud” on the underside of the epidermis, termed the follicle germ or primitive hair germ.

These mesenchymal condensations are induced by epidermal signals and that, later during development, the mesenchymal cells send messages to the epithelium, causing it to invaginate and penetrate into the dermis.

• A comparison of the follicle germ and interfollicular microenvironments reveal differences.

• For example, the follicular keratinocytes express neural cell & intercellular adhesion molecules (N-CAM) & (I-CAM), whereas these are not expressed on interfollicular keratinocytes.

• Mesenchymal cells of the dermal condensation selectively express tenascin ( to promote mesenchymal cell aggregation and epithelial cell growth) and p75 (a component of neurotrophin receptors and may be related to neuronal associations with the follicle).

II-The next stage in follicular neogenesis is known as the follicle peg which is the result of the elongation of follicle germ into a cord of epidermal cells that grows into the dermis roughly perpendicular to the skin surface.

Mesenchymal cells line the sides of the epidermal cord, and these cells eventually form the follicular sheath, while those mesenchymal cells concentrated at the tip eventuate into the follicular papilla.

• The tip of the epithelial cord is flattened and becomes the matrix portion of the bulb.

• Epithelial cells at the tip of the peg begin to show morphologic and immunohistochemical differ from epithelial cells at the upper region.

• As the follicle continues to elongate, it forms the bulbous hair peg .

• This structure is characterized by outgrowths of cells from the outer root sheath that organize and differentiate into two discrete regions on the posterior aspect of the follicle.

• The uppermost outgrowth is the presumptive sebaceous gland; the lowermost outgrowth is the bulge, which is the insertion site of the arrector pili muscle.

• The deepest portion of the bulbous hair peg forms an invagination surrounding the bulk of the underlying mesenchymal cells, which develop into the follicular papilla (“dermal papilla”).

• The matrix keratinocytes, located above the basement membrane overlying the follicular papilla, give rise to the hair shaft & the inner root sheath.

• The melanocytes responsible for pigmentation of hair are dispersed among these matrix cells.

• The outer root sheath, comprising the mostperipheral epithelial cell layers of the follicle, is in continuity with the epidermis and is most likely not formed from the matrix cells.

• As the follicle begins to produce a hair, the central cells of the rudimentary follicle degenerate, forming the path through which the hair fiber will pass.

Follicular germ stage, depicting condensation of mesenchymal cells just beneath the slight downgrowth or

“bud” of fetal basal keratinocytes.

Follicular peg stage, depicting the organization of keratinocytes in the follicle and the mesenchyme of the follicular sheath and follicular papilla located at the tip of the follicle.

Bulbous hair peg stage, depicting regions of the differentiated follicle. Two prominent bulge outgrowths are noted; the uppermost will become the sebaceous gland and the lowermost is the insertion site of the arrector pili muscle as well as the presumptive site of the hair follicle stem cells.

• The internal organization of the hair follicle is a series of concentric epithelial cellular compartments bounded by an acellular basement membrane (glassy membrane).

• The outer root sheath is the most peripheral of the cellular compartments.

• Next is the inner root sheath, which is composed of three compartments: Henle's layer, Huxley's layer, and a cuticle.

• Innermost is the hair shaft, which also has three compartments: its cuticle, the cortex that forms the bulk of the hair shaft, & the variable central medulla.

The longitudinal organization of the follicle may be divided into seven regions with distinct anatomic boundaries:

(1) The hair canal region, strictly only distinct during fetal development, extending from the skin surface to the level of the epidermal-dermal junction.

Its lower part later becomes the intraepidermal “infundibular unit.”

(2) The infundibulum extends down to the level of the opening of the sebaceous duct.

(3) Next is the area of the sebaceous gland.(4) The isthmus begins at the sebaceous duct and ends

at:

(5) The area of the bulge, the site of insertion of the arrector pili muscle and region enriched in putative follicular epithelial stem cells.

The transient portion of the follicle begins just below the bulge/arrector pili muscle complex and extends to the deepest levels of the follicle.

(6) The lower follicle includes the keratogenous zone and extends from the area of the bulge to the top of the hair bulb.

(7) The hair bulb is the deepest portion of the follicular structure and envelops the follicular papilla.

The “critical line of Auber” is at the widest diameter of the bulb & is of significance in that the bulk of the mitotic activity that gives rise to the hair and inner root sheath occurs below this level.

Another important anatomic feature of the follicle is that it lies at an angle relative to the skin surface.

The side of the follicle that forms an acuteangle with the skin surface is its anterior aspect; the side that forms an oblique angle is the posterior.

When the arrector pili muscle contracts, asin response to cold external temperature, it pulls on the posterior side.

Temporary alteration in local skin architecture gives rise to “goose bumps.”

The associated hair becomes more vertically oriented and therefore provides a greater thermal barrier, as the relative thickness of the insulating medium is increased.

The Hair Cycle

Hair follicles undergo cycles of growth, involution, & rest.

The hair follicle is not an isolated structure. It is contiguous with the epidermis, part of the

pilosebaceous apparatus, richly innervated and highlyvascularized; Likewise, the vasculature is also known to undergo changes related to the hair growth cycle.

During anagen, it traverses the entire dermis, penetrating deep into the subcutaneous fat.

Then entire skin changes during the hair cycle, with a generalized thickening during anagen (the growing phase) and a thinning during telogen (the resting phase).

During cycling, the follicle may influence the physiology of many cutaneous structures, such as the sebaceous gland & subcutaneous fat.

During anagen , the matrix keratinocytes in the bulb region proliferate rapidly, having the highest proliferative rate as compared with the other regions of the follicle.

The matrix keratinocytes can be considered as pluripotent cells because, after becoming postmitotic, they differentiate into the inner root sheath, cuticle, cortex, and medulla of the hair shaft.

Anagen is subdivided into six substages (I to VI), the first five of which are collectively called proanagen.

They are defined by progressively higher levels of new hair-tip position within the follicle.

The sixth stage, metanagen, is defined by emergence of the hair shaft above the skin surface.

The anagen follicle penetrates deepest into the skin, typically to the level of subcutaneous fat.

At the end of anagen, the follicle undergoes a series of morphologic and molecular changes that are associated with programmed cell death and apoptosis.

This stage is known as catagen. It is presently unknown what signals the onset of

catagen, although within the whole skin there is a change in the expression pattern of genes implicated in programmed cell death (apoptosis).

At the onset of catagen, the scalp hairs show agradual thinning and lightening of the pigment at the base of the hair shaft.

Melanocytes in the matrix portion of the bulb cease producing melanin, resorb their dendrites and undergo apoptosis.

Matrix keratinocytes abruptly cease proliferating and undergo terminal differentiation, so that the lower follicle involutes and regresses.

The follicular papillary cells round up and remain contained in the connective tissue sheath, which contracts, pulling the condensed follicular papilla toward the bottom of the epithelial portion of the regressing follicle.

The connective tissue sheath also becomes quite thickened during catagen.

At the end of catagen, the follicular papilla comes to rest at the bottom of the permanent portion of the hair follicle and remains there while the follicle is in the telogen phase.

The telogen hair has a club-shaped proximal end within the hair follicle and is typically shed from the follicle during telogen or the subsequent anagen.

The new hair produced from the subsequent anagendoes not “push out” the hair from the previous cycle, and may on occasion be found adjacent to a so-called retained club hair within a follicle.

The inner root sheath, which normally disintegrates in the anagen follicle at the level of the sebaceous duct opening, is totally absent from the telogen follicle.

Eventually a new growing phase occurs and the cycle is repeated.

Although the cyclic nature of hair growth described above is similar in humans and animals, the pattern of growth & rest and the rate of growth vary depending on species and body site.

For example, hair growth can occur either in a wave, where all follicles are relatively “synchronized,” or in a mosaic pattern, where the activity of each follicle is independent of its neighbors.

Humans exhibit mosaic pattern of hair cycling. Although humans also initially display a wave pattern in

utero and during the early postnatal period, this synchronization is later lost.

At 26 to 28 weeks' gestation, most human scalp hair follicles make the transition to telogen in a wave pattern that spreads from the frontal to parietal regions marking the last stage of the first hair cycle.

Many of these primary hairs are shed in utero,although this may be delayed, with resulting abundant hair at birth.

It is also typical for a bandlike area of occipital hair follicles to enter the first telogen nearer to the time of birth and for these hairs to synchronously shed 2 to 3 months later.

Waves of hair growth occur before establishment of the mosaic pattern, which is usually present by the end of the first postnatal year.

Marked variation has been reported in the length of anagen depending on body site as well as species.

In the human scalp (mosaic pattern) anagen has been estimated between 2 and 6 years, on the leg from 19 to 26 weeks, on the arm from 6 to 12 weeks, and from 4 to 14 weeks on the upper lip (mustache).

Interestingly, the hair follicles of the merino sheep are thought to be in a “permanent” state of anagen, lasting the animal's entire lifetime.

The anagen period is long (2-6 Yrs), catagen and telogen are relatively short, catagen lasting about 2 weeks and telogen between 1 and 3 months in the human scalp.

At any one time, about 85 to 90 percent of human scalp hair follicles are in anagen, about 13 percent are in telogen, and less than 1 percent are in catagen.

It is believed that each follicle goes through the hair growth cycle 10 to 20 times in a lifetime.

However, the assumption that all human follicles traverse regularly through the hair growth cycles is unsubstantiated.

Distribution of Hair

Hair follicles are distributed throughout the integument with exception of palms, soles, & portions of genitalia (so-called glabrous skin).

The highest density of follicles is on the scalp, 1135/cm2 at birth, diminishing to 795 by the end of the first year and 615 by the third decade.

The number of hair follicles in the scalp is approx. 100,000 in people with brown/black hair.

It is about 10 percent greater in blondes and 10 percent less in red heads.

Hair as a Biologic Fiber

• Mature hair shafts are nonliving biologic fibers.• The cortex is the major part of the human hair fiber and

it contains the bulk of the hairkeratins, the major constituent of hair.

• Outer root sheath cells contain several keratin intermediate filament proteins,including the K5/K14 pair characteristic of basal epidermal cells and the K6/K16 pair characteristic of hyperproliferative keratinocytes.

• In addition, K19 has also been detected in the outer root sheath cells of the adult human hair follicle, with the greatest concentration observed in the bulge region.

Other major proteins found in the cortex are known as keratin-associated proteins, which can be divided into two groups:

1- The high-sulfur protein, rich in cysteine, which form a biologic “glue” between the keratin filaments of the cortex; and

2- A less prominent group of high glycine/tyrosine –containing proteins.

Finally, there are the citrulline-containing, --glutamyl-lysine cross-linked proteins, which are found largely in the medulla.

These medullary proteins,along with trichohyalin, an intermediate filament–associated protein, are also found in the inner root sheath.

• An important biochemical feature that contributes to the physical properties of the fiber is disulfide bonding between various structural proteins.

• Such links between the keratins and the high-sulfur proteins produce a sturdy, dense network that largely fills the keratinocytes.

• These disulfide bonds also help maintain the texture and shape of the fibers; they are chemically broken during the first stage of hair styling with permanents or during straightening and reformed after the desired change has been accomplished, so that the new form is maintained.

• The cuticle of the hair shaft is also very important in maintaining the integrity of the fiber.

• It may be likened to a layer of armor that resembles reptilian scales and protects the cortex.

• When this layer is damaged from physical or chemical exposures, the fiber is more likely to break.

• When this happens along the shaft (e.g., trichorrhexis nodosa), the fiber is likely to become severed with minor subsequent manipulation; when this happensat the distal end of the shaft, the fiber is likely to fracture longitudinally, producing trichoptilosis (“split ends”).

There are also variations in the cross-sectional features of hair fibers.

Typical diameters of scalp hairs range from 40 to l20 m, with hair from whites and blacks generally having narrower diameters than hair from Asians.

There are also tendencies for scalp hairs from different races to have specific characteristics: the hair of whites is usually oval in cross section and somewhat curly; the hair of blacks is usually oval and sometimes flattened in cross section and twisted; and the hair of Asians is round in cross section and straight.

These relationships do not apply to hairs from other body sites(e.g., eyelashes, beard hairs, and pubic hairs which tend to share similar features in all races

Hair Pigmentation• The color of hair is determined by the melanocytes. • Hair is actively pigmented only when it grows, as the

melanogenic activity of follicular melanocytes is coupled to the anagen stage of the hair cycle.

• In catagen,melanin formation is switched off, and it is absent throughout telogen.

• Melanocytes located in the matrix area of the follicle, above the follicular papilla, produce the pigment.

• Pigment-laden dendritic processes from thesemelanocytes course among the differentiating hair keratinocytes, which engulf portions of the pigmented dendrites.

• A follicle usually produces only one type of pigment at any given time, 2 types of pigment can be produced.

• Eumelanin is the pigment in brown/black hairs and pheomelanin is the pigment in red/blond hairs.

• The pigment is predominantly located in the cortex of the hair shaft.

• Typically it is not found in the hair shaft during the early stages of new hair formation, and so new hair tips do not usually contain pigment.

• Similarly, pigment is typically not found in the portion of the hair shaft produced just before the follicle enters the resting phase of the hair cycle, so that the proximal portion of normally shed (“club” or telogen) hair also lacks pigment.

• One of the more perplexing issues that remains to be solved is what happens to the melanocytes during the catagen/telogen phase of the hair growth cycle.

• It is believed that they are not destroyed but remain in a shrunken, adendritic form at the base of the permanent portion of the hair follicle.

• However, it is possible that some or all melanocytes actually “die” during catagen and are replaced by precursor cells located in the outer root sheath during early anagen.

Follicular papillary cells have been found to express the agouti gene, which encodes a signaling molecule that causes hair follicle melanocytes to synthesize yellow instead of black pigment.

Expression of this gene was shown to be under two different promotors, one active at the midpoint of anagen, thus controlling the anagen-specific production of pigment.

However, the other remained active throughout the hair cycle, but only on the ventral surface, causing mice to have black dorsal hairs and yellow ventral hairs.

Another gene, bcl-2, which encodes a proto-oncogene involved in blocking apoptosis, was expressed in the follicular papillae of cycling murine and human hair follicles during the entire cycle.

Interestingly, genetic ablation of this gene in mice resulted in the formation of gray hair during the second hair cycle because of a reduced number of follicular melanocytes, suggesting that expression of bcl-2 might be essential for melanocyte survival.

Another molecule implicated in hair pigmentation is stem cell factor (SCF) and its receptor, c-kit.

Evidence for this comes from the observations that: 1- C-kit is required for postnatal melanocyte activation, 2- Melanocytes in newborn mice are c-kit dependent,and 3- Melanocytes undergo apoptosis when c-kit receptors

are blocked. Since cultured human follicular papillary cells can secrete

SCF as well as agouti gene product, these cells may play an active role in regulating the pigmentation of hair follicles.

Types of Hair

Hairs can be classified according to their texture and length; Thus, there is lanugo hair, vellus hair, intermediate hair, and terminal hair.

Lanugo hair is the soft, fine hair that covers much of the fetus and is usually shed before birth.

The other terms have most relevance to scalp hair, although the basic principles convey some meaning for other hair sites.

The classification is not exact and basically relates to the final length of the hairs: vellus scalp hairs achieve lengths less than 1 cm, indeterminate scalp hairs are approximately 1 cm in length, and terminal scalp hairs grow longer than 1 cm.

The prominence of various hair-shaft features, in general, increases with progression through this series (e.g., amount of pigment, hair-shaftdiameter, and extent of medulla formation).

Although the last three types of hair are not clearly defined in terms of fiber length for other body sites, the general relationships cited above are conveyed when such terminology is used.

• Eyebrow or eyelash hairs are typically less than 1 cm in length but are considered terminal hairs.

• Yet the usual lengths (several millimeters) of beard hairs along with their associated features in normal women would best be described as vellus hair.

• Using the phrase “terminal beard hair growth” with regard to a woman would indicate that there is a departure from the norm, with the presence of the longer,coarser hairs typical of hirsutism or hypertrichosis.

Regulation of the Hair Growth Cycle

Experimental Approaches toward UnderstandingRegulation of the Hair Growth Cycle

1- Mice deficient in transforming growth factor (TGF) or the epidermal growth factor (EGF) receptor reveal changes in the structure of the hair shaft, developing a curly or waved hair phenotype;

2-Mice deficient in bcl-2 have progressively hypopigmented hairs

3-Mice overexpressing TGF, bone morphogenetic protein 4 (BMP-4), tumor necrosis factor (TNF), interleukin 6, (IL-6) or keratinocyte growth factor (KGF) all show varying degrees of hair loss or retardation in hair growth; and

4-Mice deficient in fibroblast growth factor (FGF-5) have prolonged anagen with a long-haired phenotype.

Follicular Epithelial Stem Cells

Stem cells govern proliferation; this process plays a key role in hair follicle biology.

The bulge region of the outer root sheath is a major site of these stem cells, because epithelial cells within this region have many features characteristic of stem cells.

They have a greater proliferative capacity than epithelial cells from other regions of the hair follicle.

In addition, the bulge region is the lowermost part of the permanent portion of the follicle and thus escapes the cellular destruction that occurs during catagen; this makes it a logical region for a stem cell location.

On the basis of the identification of putativehair follicle stem cells in the bulge region, the bulge-activation hypothesis was formulated, which attempts to explain the hair growth cycle in terms of the kinetics of stem- & transit-amplifying populations.

In this hypothesis, the follicular epithelial stem cells undergo transient proliferation during early anagen, giving rise to a population of transient amplifying (TA) cells.

The TA cells rapidly proliferate, migrate downward, and eventually become the matrix keratinocytes.

Because TA cells have a limited proliferative capacity, they eventually exhaust their proliferative reserve and undergo terminal differentiation (catagen).

Involvement of the Hair Follicle in Skin Cancer Because stem cells are known to be centrally involved

in neoplastic transformation, an important issue is whether some of the skin cancers originate from the hair follicle.

Many basal cell carcinomas (BCCs) exhibit histologic and biologic features of the hair follicle.

A strong relationship has been shown between damage to the upper hair follicle induced by ionizing radiation and the formation of skin tumors in rats.

Taken together, these findings support the idea that the hair follicle is the origin of some skin tumors and that the bulge region of the follicle may be involved in early neoplastic transformation.

The Follicular Papilla As mentioned above the follicular papilla is a

specialized group of mesenchymal cells that play a central role in follicular development and cycle control.

For example, the diameter and length of the hair fiber are directly related to the volume of the follicular papilla.

Follicular papillary cells clearly send out signals that can initiate hair induction.

Follicular papillary cells produce several growth factors and cytokines that may play a role in regulating the hair growth cycle (e.g., KGF has a stimulatory effect on hair follicle growth in vivo).

mRNAs for insulin-like growth factor–binding proteins were localized to the follicular papilla and connective tissue sheath of anagen follicles, suggesting a mechanism for the modulation of insulin-like growth factor during the hair growth cycle.

mRNA for protease nexin-1, a potent serine protease inhibitor, has also been localized in the follicular papillae of anagen follicles but not in those of catagen or telogen.

Thus, the follicular papillary cells elaborate proteases and their inhibitors, extracellular matrix molecules, growth factors, receptors, and signal transduction molecules that are involved in the regulation of the hair growth cycle.

Hormones as Regulators of the Hair Growth Cycle Systemic factors can also influence the hair growth

cycle. Hamilton was the first to recognize the importance of

androgens in human hair growth when he noted that men castrated before the age of puberty neither became bald nor grew beards unless they were treated with testosterone.

Castration of older men prevented balding. Androgens are known to“upregulate” the pubic hair,

axillary hair, and beard hair but to “downregulate” genetically predisposed scalp hair follicles in androgenetic alopecia (common baldness).

The fact that only select populations of hairsdemonstrate such responses exemplifies the diverse responses of hair follicles to similar stimuli.

The follicular papilla appears to be the target for androgen effects, as these cells have been demonstrated to express androgen receptors and androgen-metabolizing enzymes.

No androgen receptors have been detected on follicular epithelial cells.

Some insight into androgen action has been gained from common forms of androgen insensitivity resulting from defects in the androgen receptor or 5-reductase (the enzyme that converts testosterone to the more potent dihydrotestosterone).

In vitro studies employing cultured follicular papillary cells from beard and scalp follicles have shown that beard cells secrete mitogenic factors when they are incubated with testosterone, which stimulates other beard follicular papillary cells and outer root sheath cells.

Similarly, beard-derived follicular papillary cells express greater amounts of insulin-like growth factor 1 (IGF-1) in response to testosterone, suggesting that IGF-1 may be a regulatory molecule in hair growth.

The Hair Follicle as a Guardian of the Epidermis Under normal circumstances, the production of a hair

fiber is the primary function of the hair follicle; however, it has long been appreciated that the follicle plays a major role in epidermal wound repair.

Evidence for this comes from observations that when the murine epidermis is experimentally removed using a felt wheel, the regeneration of the interfollicular epidermis results from the migration of keratinocytes from the hair follicle.

A similar follicular origin for keratinocytes was reported in reepithelialization of human skin following a severe burn.

While the precise origin of these follicle-derived keratinocytes has not been elucidated, recent studies on the in vitro growth characteristics of human anagen follicles provide some clues.

Keratinocytes located in the upper follicle—a region including the bulge—had a greater growth capacity than keratinocytes from the lower follicle, sebaceous gland, and, unexpectedly, even the epidermis.

This would be consistent with the idea that bulge-derived keratinocytes may be involved in the long-term maintenance of the epidermis.

In conclusion, the human hair follicle is not a functionally useless leftover of evolution or merely a cosmetic entity; rather, it plays a central role in many cutaneous processes.

The hair follicle: 1-Is responsible for forming hair, which is important in

maintaining self-image; 2-Can be active in wound repair when a major epidermal

defect needs to be covered; 3-Is a likely origin of some types of skin tumors, especially

basal cell carcinoma; and 4-May be implicated in diseases other than alopecia

areata and hirsutism, such as psoriasis which occurs primarily in hair-bearing regions.