Fig 1A-1a Pre Germ Stage. Fig 1A-1b Germ Stage. Fig 1A-1c Hair Peg Stage

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1 1 HAIR ANATOMY AND HISTOLOGY Ronald Shapiro Md, Paul Rose MD, Michael Morgan MD, Hair Transplantation 4 th Edition, Revised and Expanded, Unger & Shapiro,2004, Chapter 1A: EMBRYOLOGY Hair follicles are derived from an interaction between embryological ectoderm and mesoderm beginning around the second month of pregnancy. The earliest event is the development of regularly spaced epidermal thickenings, called placodes, initiated by molecular signaling from underlying mesenchyme. In response the overlying epidermis sends molecular signals back inducing thickening of the mesenchyme. This complex epithelial-mesenchymal crosstalk occurs throughout follicular morphogensis. The major stages of embryological hair mophogenisis are described below: Pre-germ stage (Fig.1A-1a) - The first signs of a hair follicle are an aggregation of mesenchymal cells in the superficial level of the dermis and a simultaneous thickening of basal epidermal cells immediately above it Fig 1A-1a Pre Germ Stage Germ stage (Fig.1A-1b) - At this point, the basal epidermal cells become elongated and start to bulge downward as the hair-germ, while at the same time the underlying mesenchymal cells begin to replicate to form the rudiment of what will become the dermal papilla. Fig 1A-1b Germ Stage Hair-peg stage (Fig.1A-1c) - During this stage, the epithelial cells of the hair-germ grow downward and form a column or hair peg that seems to propel the mesenchymal aggregate downward. Fig 1A-1c Hair Peg Stage Bulbous-peg stage (Fig.1A-1d) - Subsequently, three areas of swelling appear along the hair peg as the column extends downward. The most superior swelling will become the apocrine gland. The middle swelling develops into the sebaceous gland, while the lowest becomes the bulge area to which the arrector pili muscle will attach. The arrector pili forms near the developing sebaceous gland, but its development is independent of the hair follicle. During this stage, the epidermal cells at the advancing base of this column surround a portion of the underlying mesodermal cells, forming the dermal papilla.

2 2 Fig 1A-1d Bulbous Peg Stage The first primordial hair (Fig.1A-1e) - At this point the cells at the base of the column that surround the dermal papilla begin to actively proliferate, forming the early matrix, and this initial hair shaft moves upward Above this, the central cells of the follicular peg appear to degenerate, and the emerging hair seems to push out the plug so a hair canal can be formed. Fig 1A-1e Primordial Hair Stage Hair development begins at about 9 weeks and by 22 weeks the entire initial population of follicles is completed including those on the scalp. About 5 million hair follicles cover the human body at birth with approximately 100,000 being scalp hairs. It is generally felt that no new hair follicles develop after birth. On the scalp, the initial fine lanugo hairs are shed in a in a more or less synchronized wave pattern by the third or fourth month after birth. This synchronization is lost with the successive population of hairs and, by the end of the first year of life, an asynchronous population of follicles in all stages of the growth cycle exists. GROSS ANATOMY OF THE TERMINAL HAIR The hair follicle is anatomically divided into an upper middle, and lower region. These three regions are respectively termed the infundibulum, the isthmus, and the inferior segment (Fig.1A-2) The infundibulum and isthmus comprise the permanent portions of the hair follicle while the inferior segment is transient and undergoes cyclical regeneration. Fig.1A-2

3 Infundibulum - The upper region or infundibulum of the follicle consists of the area from the opening of the sebaceous duct to the follicular opening on the surface of the skin. It contains the fully formed hair shaft as it exits the epidermis. The epithelium of the epidermis is contiguous with the wall of the infundibulum. Isthmus - The middle region, or isthmus, begins at the opening of the sebaceous duct and continues down until it reaches the insertion of the arrector pili muscle. At the level of the insertion of the arrector pili is the bulge area which is very obvious in the embryonic follicle, but only intermittently obvious in the adult follicle. The bulge, considered a part of the outer rooth sheath (ORS), contains follicular stem cells that are critical for the regeneration of the FU. Recent immunohistochemical studies using stem cell markers such as CD34 and keratin15 have suggested that follicular stem cells may be more widely distributed along the ORS. The stem cells of the bulge area may, in addition, be recruited to generate epidermal and sebaceous gland cells. Interestingly, the bulge area appears to be inundated with nerve endings, as well as Merkel cells. Such a network may be involved in providing signals for hair growth and cycling. Inferior Segment - This inferior segment of the hair follicle is the area from the base of the follicle to the insertion of the arrector pili muscle. This area is transient and cyclically regenerates itself in a controlled fashion. The bottom-most portion of the inferior segment is referred to as the hair bulb and contains the rapidly dividing undifferentiated matrix cells and melanocytes which are of epithelial origin. The hair bulb surrounds the dermal papilla. The combination of the hair bulb and the dermal papilla, with its associated nerves and blood vessels, constitutes the hair root. 3 HISTOLOGY OF THE TERMINAL HAIR FOLLICLE The dermal papilla (DP) and surrounding hair matrix (HM) are located at bottom of the hair follicle. Above this the hair follicle consists (from inside out) of the following concentric layers: the hair shaft (HS), inner root sheath (IRS),outer root sheath (ORS), and perifollicular dermal sheath. The histology of these components will be discussed in more detail below. Figs.1A-3 to 5 Fig.1A-3 Fig.1A-4 Fig.1A-5 Dermal papilla - As the name suggests, the dermal papilla is of mesodermal origin. The papilla is surrounded by the matrix cells of the hair bulb. At the distal aspect of the hair bulb, the papilla connects with a fibrous dermal sheath that surrounds the hair follicle.

4 The dermal papilla contains specialized fibroblasts with powerful hair follicle inductive properties. The dermal papilla is needed for initiation of a new hair cycle and for normal hair growth. It is believed to regulate matrix cell division and the caliber of the hair produced. Androgen receptors have clearly been demonstrated in the dermal papilla. The papilla has been associated with the production of a large number of growth factors and growth factor receptors, which may play a role in hair growth. Matrix Cells - The matrix cells are located directly above the papilla. These cells are undifferentiated, actively dividing and immunologically privileged. Melanocytes are present between the basal cells of the matrix. Melanin produced by the melanocytes is incorporated into new hairs by the process of phagocytosis. The matrix cells differentiate into the multiple components of the hair follicle, including the hair shaft (HS), the inner root sheath (IRS), and the outer root sheath (ORS). These latter three structures (HS, IRS, ORS) can be visualized as three concentric cylinders embedded within each other Hair shaft - The hair shaft is the only part of the hair follicle to exit the epidermis. It in itself is also made up of three layers: a) the medulla, b) the cortex, and c) the hair shaft cuticle. a) Hair Shaft Medulla -The medulla is the most central layer of the hair shaft and probably arises from matrix cells directly above the papilla. In the supra bulbar region the cells of the medulla begin to show vesicles in their cytoplasm. At the level of the epidermis, the cells of the medulla appear to dehydrate, and the vacuoles become air filled. Terminal hairs usually contain a medulla or a partial medulla, but vellus hairs and finer hairs do not. b) Hair Shaft Cortex - Lateral to the medulla are the cortical cells of the hair shaft, which are fusiform in shape and arranged longitudinally parallel to the shaft. They become tightly packed and keratinized as they move upward. It is the cortex cells that impart the mechanical properties of hair. Pigment is present in some cortical cells. This pigment was initially aqquired through phagocytosis from melanosomes in the matrix c) Hair Shaft Cuticle -The cuticle is the outermost layer of the hair shaft and is composed of 6 to10 layers of overlapping cuticle cells. They are arranged in a shingled type of array and later become keratinized and point upward, so they can interlock with the downward projecting cuticle cells of the surrounding inner root sheath. Inner Root Sheath - The inner root sheath (IRS) surrounds the hair shaft. It exists only in the inferior segment of the hair follicle traveling from the bulb up to the beginning of the isthmus,, Beyond the erector pili muscle, the keratinized IRS deteriorates and is replaced by keratin from outer root sheath (ORS). The IRS is also made up of three layers: a) the IRS cuticle, which is one cell thick; b) Huxley s layer, which is three or four cells thick; and c) Henley s layer, which is also one cell thick. As the cells in the IRS keratinize, they give rigidity to this sheath, supporting the IRS function as a mold for the enclosed and developing hair shaft. Racial differences in shaft cross section shape and size are determined by the IRS. The IRS is tightly moored to the hair shaft by the overlapping of cells from their adjacent cuticle layers. The hair shaft and IRS move upward together slipping along the surrounding the innermost layer of the ORS. Outer root sheath - The outer root sheath (ORS) surrounds the IRS and consists of multiple layers of epithileial cuboidal cells containing large quantities of glycogen. It travels from the bottom of the hair bulb to the opening of the sebaceous duct. It is thinnest at the level of the hair bulb and thickest 4

5 at the isthmus. The outer root sheath contains melanocytes, neuro-secretory cells (Merkel cells), and Langerhans cells and is also proposed site of follicular stem cells. Dermal Sheath - Outside the outer root sheath, a vitreous, PAS positive, hyaline membrane layer is evident. Collagen bundles from the dermis surround this layer to form the perifollicular dermal sheath. KERATINIZATION Keratinization of the hair follicle occurs in an organized fashion that helps mold and shape the hair shaft. First the inner root sheath (IRS) keratinize with tychohylaline granules starting with Henle layer and followed by the cuticle and Huxley layer. This creates a firm mold surrounding the cortex and medulla of the hair shaft. Next the cells of the cortex cells degenerate and fill with keratin fibrils. The medulla is last to cornify. 5 INNERVATION AND BLOOD SUPPLY Hair follicles are innervated by nerves that course from the bulb to the epidermis. Some hair follicles possess a hair-end organ. This anatomical structure is made up of a collar of nerves that surrounds the hair follicle at the level of the sebaceous gland. Hordinsky and Ericson have demonstrated that cells in and around the dermal papilla stain, with a pan-neuronal antibody, and that substance P can be detected at the bulge area and perifollicular nerves and vessels. Such observations provide more evidence that suggests there may be neural signals that influence hair physiology. Hair follicles have an abundant blood supply. Vascularization is pronounced in the upper and lower portions of the follicle, with vessels penetrating the papilla. THE FOLLICULAR UNIT In 1998, Headington published a paper describing the transverse anatomy of hair follicles. He demonstrated that hairs at the level of the sebaceous duct appear to exist in groupings, which he termed Follicular Units (FU). Headington defined an FU as consisting of two to four terminal follicles and one or more vellus hairs, as well as the associated sebaceous glands, insertion of the arrector pili (AP) muscle and the surrounding perifollicular demal sheath. These groupings are obvious from the surface to the level of the AP muscle insertion. Below this level the individual follicles tend to separate in the fatty layer making the groupings less obvious (Fig 1A-6&7) Recent three-dimensional reconstructions by Poblet, Ortega, and Jimenez (2002) of the FU provide evidence and support the idea that a single AP muscle inserts into every follicle in a FU. Additionally, the AP muscle was found to be concave at its base, near the point of insertion. The concavity is believed to provide structural support to sebaceous lobules that fill the space, between the hair follicle and AP muscle. There is also evidence for the role of the AP muscle as a tie that binds all the individual hair follicles in a FU together at the level of the isthmus.

6 6 Follicular Unit density on the scalp is currently felt to average between 75 to100 FU/cm2 although it may range higher or lower. A follicular unit can contain between one to five terminal hairs but the majority (~80%) contain one to three terminal hairs. Variations in density exist at different locations on the scalp and in different ethnic groups. Fig.1A-6 Fig.1A-7 VELLUS VS TERMINAL HAIR Hairs may be termed vellus or terminal depending on a number of characteristcs including length, diameter and pigmentation and location of the root. Vellus Hairs- Vellus hairs are small, soft hairs with a diameter less than.03mm and a length less than 1 cm. They have no pigment or medulary cavity and are often rooted in the superficially in the upper dermis Depigmented hairs that are less than.03 mm and have been miniaturized by androgenic alopecia, or any other cause, can be classified as vellus like hairs. The term vellus hairs are often used to include both true vellus hairs and vellus-like hairs. At puberty, vellus hairs are replaced by terminal hairs in certain areas of the body axilla, pubis, and face), and this change occurs by means of androgenic hormones. Terminal hairs - Terminal hairs are larger hairs with a diameter exceeding.06 mm and a length greater than 1 cm.. The are often pigmented and medullated, They are rooted in the subcutaneous or deep dermis layer. It is sometimes useful to differentiate intermediate hairs, between.03 and.06 mm in diameter, which may represent early miniaturization of terminal hairs, as seen in androgenic alopecia. The normal ratio of terminal to vellus hairs in a normal scalp is 7:1. HAIR CYCLE Each hair follicle goes through the hair cycle10-20 times in a lifetime, every cycle recapitulating much of the embryological development. The hair cycle is classically composed of three distinct phases: anagen (growth) phase, catagen (involution phase) and telogen (resting) phase. (Fig.1A-8). A fourth exogen stage has been described recently, although it remains a source of controversy as to if it truly represents a separate stage in the hair cycle. Anagen ge nerally lasts from three to ten years, catagen two to three weeks, and telogen three to four months. In the human scalp, the cycle is asynchronous. At any one time, an average of 13% of the hair is in telogen, although it can range from 4-24%. Only 1% is in the catagen phase. Neighboring hairs within a follicular unit may be in different stages.

7 7 Fig.1A-8 Anagen to Catagen At the end of the anagen (growth) phase, the hair follicle receives an unknown signal to enter the catagen phase. The matrix cells cease proliferating, and the production of melanin terminates. The dermal papilla contracts and is released from the follicle. The middle portion of the follicle constricts and the lower portion expands to become the club hair. This lower portion retracts up to the level of the erector pili muscle leaving a behind a thin band ( streamer ) of undifferentiated epithelial cells. The mechanism of retraction is felt, in part, to be due to apoptosis (controlled cell death). Although the exact signal for the induction of catagen is not known, factor 5 (FGF5) has been implicated; in animal models without this factor, catagen is delayed Catagen to Telogen The catagen phase is generally less than 4 weeks in duration and, therefore, is difficult to distinguish it from an early telogen phase. Specific molecular signaling aiding in this transition have not yet been characterized. Telogen to Anagen During telogen, the band of epithelial cells (streamer) left behind during catagen moves upward and forms a short projection underneath the club hair called the secondary hair germ (HG). This path upwards is followed by the dermal papilla, whose size is currently greatly reduced at this stage. At some point anagen is initiated by complex molecular signaling occurring between the dermal papilla, secondary hair germ (HG) and stem cells from the bulge area. This signaling triggers stem cells to become transcriptionally active and migrate to the HG. The DP enlarges and the hair germ exhibits proliferation and downward growth eventually enveloping the enlarging DP. A new hair bulb is formed and anagen progresses. Current evidence suggest that regulation and transition into anagen phase depend on the careful interplay of BMP, FGF7, and Wnt/ β-catenin pathways Exogen The exogen phase begins with the completion of a club hair and ends with its release. Actual loss of the club fiber signals the end of the exogen phase. The term teloptosis has been used to describe the actual release of the club fiber, and the term kenogen has been used to denote the period of telogen without a hair club in the follicle. The exogen phase is considered to be a closely regulated, independent, cycle phase, although the exact molecular mechanism has not yet been described. On the receipt of an unknown signal, proteolytic enzymes may convert the previously tightly held hair shaft within the bulbous base of the follicle into a slenderized, more spear-shaped exogen bulb, which facilitates shedding of the hair.