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Hair
follicle cycle
The hair follicle is an integral component of the
skin, and each hair is a keratinized product of the follicle.
Each and every
hair follicle undergoes a cycle of activity - The hair grows to
a maximum length, then hair growth ceases and the hair is shed
and replaced. This characteristic three-part cyclical growth pattern
of hair is the result of follicular activity, which is not obvious
by casual inspection. The phases of the hair growth cycle have
been described as:
1. Anagen, a long period of growth
2. Catagen, the transitional period from growing to resting lasting
2 to 4 weeks
3. Telogen, a period of inactivity lasting 2-4 months
The relative duration of these phases varies with the individual's
age, nutritional status, hormonal factors, and other physiologic
and pathologic factors. Although the duration of anagen determines
the final length of the hair and thus varies according to body
site; the duration of catagen and telogen phases vary to a lesser
extent depending on site. Unlike other mammals, hair growth and
loss in humans is random and not seasonal or cyclic. At any given
time, a random number of hairs will be in various stages of growth
and shedding. Determining the molecular signals that orchestrate
the follicle’s transit between these stages is one of the
key challenges of hair research.
The catagen phase in the hair follicle cycling process
can be described as a highly controlled process of coordinated
regression and apoptosis. The phase involves the cessation
of cell growth and pigmentation, release of the papilla from the
bulb, loss of the layered differentiation of the lower follicle,
substantial extra-cellular matrix remodeling, and shrinkage of
the inferior follicle primarily by the process of apoptosis.
Since early anagen termination results in unfavorable conditions
like alopecia and telogen effluvium, and late catagen onset leads
to hirsutism and hypertrichosis, the control of catagen
from the
clinical aspect
of hair loss disease and hirsutism is of great importance. The
controls of catagen-associated keratinocyte apoptosis and of dermal
papilla
activities are currently
under
study as crucial targets for future therapeutic manipulations
in hair diseases.
Catagen
in the hair follicle cycle
Catagen is the transitional phase in the hair growth cycle,
and there are chemical and structural changes that take place
in the
hair follicle during this phase. The hair follicles go through
a highly controlled process of involution, which is a process
of progressive decline or degeneration. The involution process
largely brings about a burst of programmed cell death (apoptosis)
in the majority of follicular keratinocytes. Follicular melanogenesis
(formation of melanin) also ceases during this stage, and some
follicular melanocytes undergo apoptosis as well. Towards the
end of the catagen stage, the dermal papilla condenses and moves
upward, coming to rest beneath the hair-follicle bulge.
Observations in both murine models with mutations of the hairless
gene and human studies show that if the dermal papilla fails to
reach the bulge during the catagen stage, the follicle stops cycling
and the hair follicle is lost. This gene encodes for a transcription
factor whose disruption prevents the dermal papilla from ascending
and
interacting with the stem cells of the bulge, resulting in permanent
alopecia. During the catagen stage in mice, a few hair follicles
are also destroyed by an inflammatory cell infiltrate, in an apparently
physiologic process of programmed organ deletion.
Like anagen, catagen is a highly regulated event, in its initiation,
development, and termination. The purpose of catagen is to delete
the old hair shaft factory and to initiate the stem cells of the
bulge and the papilla to set the stage for the formation of a
new follicle.
Mechanism
of catagen
As soon as the growth phase (anagen) is complete, follicle growth
stops and degeneration begins. Why the cycle ends as and when
it does is one of the most fundamental questions of hair biology
which remains unanswered. The unidentified signal may either be
inherent in or delivered to the follicle, causing involution at
a surprisingly rapid rate. Although the spontaneous inductive
signals that cause catagen have yet not been identified, there
is evidence to support that severe stress characteristically precipitates
catagen. Environmental factors, such as trauma, chemicals, experimentally
administered endogenous hormones, like Adrenocorticotropic hormone
(ACTH) and 17b-estradiol can induce catagen.
The catagen stage of the hair cycle has been divided into eight
sub phases beginning with late anagen and ending in early telogen.
Extensive destruction of the lower follicle marks the onset of
catagen and the first indicator of regression in the catagen follicle
is the withdrawal of papilla cell fibroblast projections from
the basement membrane. The papilla shrinks, probably through the
loss of extra-cellular matrix substance.
At the same time matrix and lower outer root sheath keratinocytes
abruptly stop proliferating and undergo apoptosis. Melanocytes
stop producing pigment before matrix cell proliferation stops,
thus leading to a non-pigmented proximal tip to the telogen club
hair. In addition, the production of cytoskeleton proteins of
follicle epithelial cells, namely trichohyalin, transglutami-nase-I,
and desmoglein, ceases.
Simultaneously there is progressive shrinkage of the lower follicle,
which withdraws as an epithelial strand. The largest follicles,
(those on the scalp for example), shorten their length from 2-5
mm long structures which extend into the subcutaneous fat, to
shortened 0.25-0.5 mm follicles confined to the dermis in telogen.
The basement membrane thickens dramatically, and the lower follicle
retracts upward with the dermal papilla. The perifollicular sheath
collapses and forms a fibrous streamer comprised of fibroblasts
(connective tissue cells), small blood vessels, and collagen (fibrous
protein that makes up connective tissue).
Meanwhile the outer root sheath within the isthmus (middle segment
of the hair follicle) becomes rounded and surrounds the bulbous
terminal portion of the hair. As the lower follicle slowly degenerates,
the outer root sheath loses its glycogen (carbohydrate storage)
and the inner root sheath disappears. The outer root sheath keratinizes
or hardens, forming a ridged thick eosinophilic layer which anchors
the lowest portion of the hair shaft. At the end of catagen, the
thickened basement membrane of the hair follicle disintegrates
and is replaced by one of normal thickness.
There is evidence to support the fact that the migration of the
dermal papilla from the subcutaneous fat to the dermis during
catagen is essential for continued follicle cycling. People with
a congenital or acquired absence of hair (known medically as atrichia)
have mutations in their hairless gene or in their
vitamin D receptor gene, and studies indicate that mice with similar
mutations have the hairless phenotype. In atrichia, folliculogenesis
(the process by which follicles are first formed in the ovaries
before birth) is normal; however, when the follicles enter catagen
for the first time, the lower portion does not involute and contract
properly, and the dermal papilla remains stranded in the subcutaneous
fat. Although bulge cells are still present, no new anagen follicles
ever form, presumably because the stem cells cannot interact with
the dermal papilla.
Experiments conducted on mouse mutants have thrown light on the
anagen-to-catagen transition. Hebert et al were successful in
discovering that fibroblast growth factor-5 (Fgf5) may trigger
catagen onset. Mouse experiments have shown that total skin Fgf-5
expression increases in late anagen and that, in its absence,
catagen induction is delayed prolonging anagen. The fact that
Fgf5 is expressed in high concentrations during mid anagen and
in low concentration during late anagen VI, catagen, and telogen
could explain the mechanism of this important pathway. There are
other molecules that could serve as anagen-supporting signals.
During anagen-catagen transformation, there is also an increase
in the number of deeply situated perifollicular mast cells. (Mast
cells play an important role in the body's allergic response).
Apoptosis
in catagen
Apoptosis refers to a highly controlled form of cell death where
the affected cell implodes, and is a crucial factor of hair cycling.
Apoptosis presents characteristic morphological changes including
cell shrinkage, loss of cell-cell contacts, condensation of chromatin
(structural building block of a chromosome), collapse of the skeleton
contained within the cytoplasm, nuclear contraction and fragmentation,
cytoplasmic eosinophilia, cell fragmentation, and phagocytosis
(cell eating) by reactive histiocytic (cells that are part of
the human immune system) or adjacent cells in the tissue in which
apoptosis occurs.
At present it is not clear what exactly initiates the apoptotic
processes in catagen, or even where the signal arises. Insulin-like
growth factor IGF-I receptor expression by the dermal papilla
appears to be
switched off during the transition from anagen to catagen, which
implies a regulatory role for IGF-I during the hair growth cycle.
Neurotrophins are a family of molecules that encourage survival
of nervous tissue, and the neurotrophins, NT-3, NT-4,
and BDNF as well as TGF- 1 all have recently been identified as
crucial catagen-promoting agents.
Catagen
in the hair follicle cycle references
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