The article below is by Dr. Richard De Villez, one of the original physicians helping to coordinate Upjohn's Minoxidil FDA trials. He is one of the leading experts on hairloss in the United States.

Richard L. De ViIIez, MD

Associate Professor
Division of Dermatology
University of Texas Health Science Center
San Antonio, Texas

Contents

Microstructures of the Follicle and Hair 


Actively growing hair follicles penetrate the entire epidermis and dermis;
and on the scalp, these follicles extend into subcutaneous adipose tissue. At
its lower end, the follicle expands into the bulb whose ovoid central cavity
is filled by a connective-tissue papilla.

The Hair Bulb 


The dermal papilla (the connective tissue within the invagination at the
bottom of the hair bulb) has an abundance of cell components, which include
fibroblasts, histiocytes, melanophages, mast cells, and Langerhans'
granule-containing cells. The papilla also contains a loose texture of
fibrous elements. The dermal papilla is supplied by a profuse system of small
blood vessels, which are comparable with subepidermal capillaries. Their
vascular walls are lined by a single layer of flat endothelial cells that
rest on a distinct basal lamina, which is incompletely surrounded by
pericytes. The intercellular junction of the endothelium contains an
intermediate junctional complex. The flat endothelial cells are frequently
fenestrated by 0.1-um pores.14 The pores are irregularly spaced and are
closed by a thin diaphragm, which appears to be continuous with the cell
membrane. Near the base of the follicle, the vascular basal lamina consists
of at least two or three thin membranous layers, which show no age-related
variations. The basal lamina in the dermal papilla, however; is characterized
by concentric multilaminations that range from two to more than 20 layers,
each of which display an onionskin-like arrangement. These concentric
multilaminations are not prominent in individuals 10 years of age or
younger; but in older individuals, these features are significant and
unmistakable. 

Thickening of the perivascular basal lamina is a physiologic effect of aging, and it 
characterizes various disease conditions, including diabetes mellitus.14  
Extensive accumulation of basal lamina in capillaries has been noted in patients 
who have diabetes mellitus, and this accumulation appears to be the result of 
repeated episodes of endothelial injury. When examined by alkaline phosphatase 
techniques, dermal papillae in telogen reveal no capillaries.  

When telogen follicles become anagen again, the developing hair bulb advances 
through the collapsed vessels below the dermal papilla, and a new vascular 
network is generated. As catagen proceeds, the blood vessels still remain intact, 
but they finally disappear from the dermal papilla; and the lower plexus forms a 
tight bundle of vessels around and beneath the papilla. It can be argued, 
therefore, that the amount of concentric multilamination of the perivascular 
basal lamina, in the dermal papilla of human bait; intimately relates to the 
episodes of repeated death and regeneration of endothelial cells and to the 
number of hair cycles.14  

Connective-tissue cells of dermal papillae are separated from follicular epithelia 
by basal laminae, the continuity of which is interrupted only rarely by 
pseudopod-like extensions of basal cells.12 The mesenchymal cells in the dermal 
papilla are attached together at sites along their plasma membranes, and this 
forms an intermediate junction. The function of the attachment sites is unknown; 
but, presumably they allow the cells to work in concert. Because it is likely that 
control of cell growth is, at least in part, biochemical in nature, intracellular 
substances that alter growth and development preferentially pass through these 
junctions.  

However, "gap" junctions have never been found. It has been noted that hair 
follicles devoid of a dermal papilla fail to form hairs. If dermal papilla cells are
transplanted to the base of a hair follicle that has a severed matrix, a new matrix 
will form and produce hair.15

 Two forms of concentric lamellar bodies have been observed14 in the
cytoplasm of mesenchymal cells in the dermal papilla of normal anagen scalp
hair: (I) those composed of agranular membrane arrays that are associated
with beta- glycogen particles (known as glycogen lamellar bodies) and (2)
those with a smooth-surfaced endoplasmic reticulum (known as smooth surfaced
concentric lamellar bodies). Both forms have been found in mesenchymal cells
of dermal papillae and in other types of cells in a wide variety of animals.
No specific significance has been found for these cytoplasmic structures and


figure 2. Distribution of mitotically active cells in bulb of anagen follicle


no consistent relationships have been documented between cell type and the
forms of lamellar bodies studied. The formation of these cytoplasmic
structures could result from the degeneration of cells after injury or it
could indicate a recovery process rather than a degenerative event.  

The second portion of the hair bulb involves the hair matrix, which consists of
rapidly dividing cells in the base of the bulb and is the part that  surrounds the 
dermal papilla. The proliferative zone is the annular matrix in the portion of the 
bulb located below the "critical" level (Auber's line), i.e., below a line passing 
through the widest diameter of the papilla (Figure 2). Mitosis also occurs in a 
few of the germinal cells of the bulb above the apex of the papilla, but the bulk 
of mitotic activity occurs in the lower portion of the matrix. The nucleus of a 
matrix cell is large and spherical, and many ribosomes and mitochondria are 
located within its scanty cytoplasm. These cells are rich in RNA and contain 
desmosome attachments and gap junctions.  Each matrix cell may divide every 
23 to 72 hours during the anagen phase.  


figure 3. Differentiation of cells in bulb


In the pre-elongation zone above the critical level, the cells first enlarge and
then align themselves in a vertical direction. The cells that surround the
dermal papilla are precursors of the hair fiber, and the peripheral matrix cells 
form the internal root sheath (Figure 3).  

In the cellular elongation zone of the supra bulbar portion of the follicles, the 
cells become long and thin with distinct boundaries. Above this zone, in the 
prekeratinization zone, they acquire basophilic fibrils.  The overall size of the 
cells and the relative amount of cytoplasm they contain noticeably increase as a 
result of their increased water content and increased intracellular protein 
synthesis. The nuclei and nucleoli remain prominent in this zone.17  

Melanocytes, with few dendritic processes but with a dense accumulation of 
melanosomes, are located above the apex of the papilla, at the upper pole of the 
bulb. The dendrites project into the intercellular spaces between the developing
medullary cells and cortical cells. In the phase of differentiation, parts of
the dendrites (together with melanosomes and pigment granules) are
phagocytized and migrate into the cytoplasm of the medullary and cortical
cells.11,18 

Medullary cells do not produce significant amounts of protein, but
they do produce some filaments that aggregate into bundles and become
randomly distributed in the cytoplasm. As differentiation proceeds, glycogen
granules appear particularly near the nucleus. In the final stages of
differentiation, the nucleus and other cytoplasmic organelles begin to
disintegrate. Fully formed medullary cells become wedged between projections
of cortical cells; and in fully developed hair, these cells are spaced along
the hair's core. Vellus and lanugo hairs contain no medullary cells, and even
terminal hair follicles may not contain medullary cells. 

When hair bulbs are treated with arachidonate, melanocyte complexing and 
dissolution are altered.18 This evidence suggests that arachidonate, through the 
production of endogenous prostaglandins, may stimulate the dispersion of 
melanosomes into the dendritic processes of melanocytes by peripheral 
orientation of the microfilaments in the hair-bulb melanosomes.18

Cortical Cells 


Cortex cells come from the concentric ring of germ cells localized in the
bulb immediately above the apex of the papilla (Figure 3). Their successive
keratinization occurs in the keratinization zone (Figure 4). In the lower
segment of the keratinization zone, these spindle- shaped cells produce
cytoplasmic filaments that are parallel with both the long axis of the cell
and the hair follicle. Intense protein synthesis is evidenced by the
occurrence of large numbers of polysomes and by strong nucleolar and 
cytoplasmic staining of RNA.19 The filamentous material is generally high in
molecular weight (45,000 to 60,000 daltons) and low in sulphur content; it
also has between 30% and 60% helical content (as measured by optical rotary
dispersion or circular dichroism).20 These materials aggregate into dense
alpha-keratin fibrils that have no obvious connection with the tonofibrils.
Matrix material forms a bed in which the filaments are arranged in an
organized fashion. It is thought that these two types of materials are
connected by disulfide bonds. 

The matrix material appears to be (1) much more heterogeneous, (2) lower in 
molecular weight, and (3) of consistently higher sulphur content than that found 
in the filaments.21 Halfway up the keratinization zone, tonofibrils begin to 
increase in number, and the rate of protein synthesis decreases. The amount of 
RNA diminishes and finally disappears at the distal end of the keratinization 
zone. The quantities of cysteine and phospholipids increase as an apparent 
consequence of cell membrane degradation. During cytolysis, nuclei lose their 
DNA, mitochondria and ribosomes degenerate, and incomplete nuclear-
membrane structures are left behind in the cytoplasm. Above the keratinization 
zone, cysteine is converted to cystine, and the cell membrane becomes thicken 
The diameter of the fully keratinized hair decreases by 25% because of (I) the 
loss of water that results from the permeability of the plasma membrane and (2) 
the contraction of the keratin complex. The fully keratinized, dead cortical cells 
retain a membranous nuclear outline (nuclear ghost) that persists into the hair 
shaft.  At this level, the prevalent -SH groups in the pre-keratin are replaced by
S-S bonds.21


figure 4. Zones and layers of hair bulb

Hair Cuticle 


Hair cuticles originate from primordial bulb cells that contain amorphous
cytoplasm granules. The cuticular cells elongate in the suprabulbar region
and become flattened (Figure 4). During differentiation, the cells
increasingly overlap. Tonofibrils and desmosomes are present, but no
alpha-keratin fibrils are observed. During hardening and keratinization,
dense cytoplasmic granules are visible, and cystine disulfide groups are
detectable. These groups form a matrix rather than fibrillar protein
structures. The cuticular cells contain no fibrils, and the cystine matter in
their cytoplasm is amorphous. The overlapping cells of the cortex's cuticle are 
directed outward, and they interdigitate with the cuticular cells of the inner root 
sheath.  

The cells of the hair medulla, cortex, and cuticle all cornify without prior 
formation of keratohyalin granules or trichohyalin granules.22

Inner Root Sheath 


The inner root sheath consists of three layers: the cuticle, Huxley's layer,
and Henle's layer The cuticle is one cell-layer thick, the thickness of
Henle's layer is one to two cells, whereas Huxley's layer is several cells
deep (Figure 4). All three layers are formed from the peripheral mass of
matrix cells in the hair bulb (Figure 3), and they undergo differentiation
and hardening at different rates. These changes occur first within Henle's
layer, then within the cuticle, and finally within Huxley's layer. The final
stage of differentiation involves the disintegration of the nucleus while
other organelles and the trichohyalin become diffusely distributed as dense
materials between keratin filaments. Complete hardening and differentiation
occur in the inner root sheath before they occur in the layers of the
developing hair. The hardened regions of the medulla and inner root sheath
strongly indicate the presence of citrulline whereas trichohyalin is no
longer demonstrable.  

When stain tests are used to detect the presence of arginine, the trichohyalin 
stains intensely.21 During the final stages of differentiation, some of the protein-
bound arginine residues of trichohyalin are converted into protein-bound 
citrulline of the hardened proteins. This is particularly evident in the cuticle of 
the inner root sheath.21  

The junction between the outer root sheath and the Henle layer is maintained by 
desmosomes and gap-junctions; and at the end of differentiation, this junction is 
maintained by intercellular cement and interdigitation between cells. Upon 
maturation, the inner-root-sheath cells deposit amorphous intercellular material 
and cause thickening of the plasma membranes. Cells shrink during 
keratinization, and the mature inner root sheath becomes a rigid cylindrical tube 
that surrounds the soft, ascending hair structure. The primary function of the
inner root sheath is to shape the hair contained within it. Because the
cuticles of the hair and the inner root sheath are closely apposed, the fully
keratinized hair assumes the shape of the inner root sheath. At the level of
the follicular canal, desmosomal contacts between adjacent cells begin to
break; and the cells, either singly or in groups, are shed into the
follicular canal (Figure 5).20

Outer Root Sheath 


The outer root sheath surrounds the hair follicle (much like a sleeve), is
several layers thick, and is continuous with the epidermis (Figure 4). It has
two characteristic proliferation zones: (1) in the bulb and (2) in the basal
layer of the epidermis. Two layers of cells surround the bulb; and during
formation of the anagen follicle, vertical upward growth predominates. The
outer layer of the cell is germinative and continuous with the epidermal
basal cells, and differentiation occurs by the horizontal movements of
cells from the basal layer of the outer root sheath to the center of the
follicle.


figure 5. Zone of sloughing


 Subdivision of the two proliferative zones reveals that the cells are
significantly different: (1) those cells derived from the bulb are
cylindrical and their long axis parallels the direction of hair growth and
(2) those cells derived from the basal layer are irregularly shaped, and
their cytoplasm contains many vacuoles.11,23 The outer-root-sheath cells
nearest Henle's layer flatten and undergo autolysis. The exact fate of these
cells is not known; however, movement toward the surface probably occurs, and
they are probably shed into the follicular canal along with the inner root
sheath (Figure 5). 

Keratinization of the outer root sheath occurs in those areas of the hair follicle 
where it is not apposed to the inner root sheath.23 These areas are (1) in anagen 
hair, located between the insertion of the hair erector pili muscle and the
opening of the sebaceous duct (Straile's zone of sloughing) and (2) in catagen 
hair the sac of epithelium that surrounds its lower end after the inner root 
sheath has disappeared.23 This process is called trichilemmal keratinization, and 
it is the end product of the outer sheath; therefore, it is not derived from the 
hair matrix but from stratified squamous epithelium,23 which is transformed 
into nonnucleated keratinized cells without forming a keratohyalin layer. In 
catagen hair a trichilemmal sac surrounds the lower end of the dying hair shaft, 
and there it forms the club of telogen hair.  Also in catagen hair as the outer root 
sheath undergoes trichilemmal keratinization, it converges on and occasionally 
fuses to the cortex of the remaining hair. This "brush" consists of keratinizing 
cells of the outer root sheath, which becomes elongated rather than flattened
similar to the zone of sloughing of the anagen follicle. The function of the
outer root sheath is not known.

Connective-Tissue Hair Sheath 


The connective-tissue hair sheath is an important physical support of the
hair follicle. In the follicle of anagen hair the structure of the upper half
of the connective-tissue sheath differs from that of the lower halt, which
changes during the growth cycle. Between the epidermis and the
sebaceous-gland layer fine collagenous fibers are arranged longitudinally
around the upper half of the hair follicle.24 Around the lower half, the
connective-tissue sheath consists of fine collagenous fibers that are
arranged circularly in the inner layer and longitudinally in the outer layer
Prominent elastic filaments develop in the upper half of the
connective-tissue sheath, but only a few elastic fibers are present in the
lower half. The brush-like filaments that project into the dermal papilla and
the circular filaments that occur in both the dermal papilla and its basal
plates are present in most hair follicles. These fine, brush-like filaments
appear to be connected to the longitudinally arranged fibers in the outer
layer of the connective-tissue sheath, and the circularly arranged elastic
filaments appear to be connected to those fibers of the inner layer. These
elastic-like bodies occur in the follicles of adolescents, but they diminish
with age.24

Amino Acid Analysis of Hair 


Fibers of human hair are extremely complex; and, morphologically, they
consist of several different chemical species. Amino acids that comprise the
peptide chain, which forms the basis of the keratin molecules, are readily
available in the body. For synthesis of follicular proteins, the most
important amino acids are those that contain sulfur i.e., predominantly
cystine, because it forms stable disulfide bonds between keratin molecules.
Table 2 indicates that cystine is the amino acid of highest concentration in
fully formed bait The cortex occupies the primary volume of human hair and
contains the principal structural proteins, which are insoluble and contain
extensive cystine disulfide cross-linkages (hard keratin).

Table 2
Histochemistry of hair

Cystine	Disulfide cross-links. distal
		keratogenous zone

Cysteine	Sulfhydryl groups, proximal
		keratogenous zone

Arginine	In association with trichohyalin
		of inner root sheath

Citrulline	Hardening products of inner root
		sheath and medulla

DNA		Matrix cells and dermal papilla

RNA		Basal cells of outer root sheath,
		medullary cells


Analyses of the fibrous proteins and matrix proteins of an entire human hair 
reveal that the matrix proteins contain high concentrations of sulfur and the 
filamentous proteins contain low concentrations of sulfur.25 No citrulline is 
found in the cortex of hair.

Proteins located in the medulla and the inner root  sheath differ from cortical 
proteins. The large percentages of citrulline and glutamic acid found in 
medullary proteins indicate that these substances are not keratins and that they 
are synthesized differently than cortical proteins. Arginine residues from 
trichohyalin are converted to protein-bound citrulline of hardened proteins.21 
These proteins contain typical lysine bonds, which occur neither in the hair 
cortex nor in the cuticle.11

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