What
regulates hair growth
All mature follicles enter into a pattern of cycling. There are
three main stages of hair follicle cycling - anagen (growth),
catagen (regression) and telogen (rest). Subsequently the hair
shaft is shed. This process is called exogen. The cycle differs
from species to species and from follicle to follicle. Animals
like
sheep (except merino sheep) have
a seasonal replacement of hairs twice a year whereas in mice it
can be more frequent at 6 or more times a year. The regeneration
and replacement of hair is not always apparent to
the naked eye.
As old hair is shed it normally gets replaced and the cycle seems
seamless. The only way to really look at hair cycling is through
experiements that involve looking at the hair follicles themselves.
Observations and studies, mostly in mice, have led to some insight
on the
factors that
regulate the hair follicle cycling, but there is no one factor
that can be said to be having ultimate control over hair growth.
Although human hair follicles apparently cycle through growth
and rest independently of each other there must a biological
mechanism to promote anagen hair growth and the involution of
the hair follicle
to a resting stage. Clues to the basics of this mechanism have
been known about for many years. Any form of skin damage will
force telogen hair follicles in rodents into anagen growth in
and around the site of injury. Any skin damage induces temporary
hair growth. As the injury heals so the hair follicles go back
to normal. There is similar evidence that
skin injury in humans will also promote growth
and induce
anagen
in hair follicles nearby if hair
follicles
are
in telogen. Hair growth stimulation can come from cuts, scrapes,
heat/chemical burns including sun burn, limited local necrosis,
and some forms
of skin irritation. So long as the hair follicles are not significantly
damaged, then mild skin injury seems to promote hair growth. In
part, this activation of growth is probably due to an increase
in cytokines
(signaling chemicals) due
to the skin injury and damage.
There are too many factors that affect hair growth to list them
all here. Various pages on this site list different groups of
factors
that modify hair follicle activity. In terms of products naturally
produced by the body, the key factors that affect hair growth
are
hormones and cytokines. Hair follicles have receptors for androgens
and estrogens that can each affect hair follicle activity. Other
hormones including those derived from the thyroid and the pituitary
glands can also have significant hair growth effects. In addition,
there are
other naturally produced chemcials called cytokines that act on
cells in a hormone-like manner. Below is a table listing some
hormones
and the more common cytokines and their action on hair follicles.
| Endogenous substances that affect
hair growth |
| Substance |
Site of action |
Effect on hair growth |
|
Basic fibroblast growth factor (bFGF)
|
Dermal papilla
|
Increase
|
|
Platelet-derived growth factor (PDGF)
|
Dermal papilla
|
Increase
|
|
Transforming growth factor beta (TGF- beta)
|
Dermal papilla
|
Decrease
|
| Hepatocyte Growth Factor (HGF) |
Dermal papilla / Hair matrix |
Increase |
| Macrophage Stimulating Protein (MSP) |
Dermal papilla / Hair matrix |
Increase |
|
Interleukin 1-alpha
(IL-1- alpha)
|
Hair matrix
|
Decrease
|
|
Fibroblast growth factor type 5 (FGF5)
|
Hair matrix
|
Decrease
|
Vascular Endothelial Growth Factor (VEGF) |
Hair matrix |
Increase |
|
Epidermal growth factor (EGF)
|
Hair matrix
|
Decrease
|
|
Keratinocyte growth factor (KGF)
|
Hair matrix
|
Increase
|
|
Insulin-like growth factor I (IGF-I)
|
Hair matrix
|
Increase
|
|
Substance P
|
Unknown
|
Increase
|
|
Parathyroid hormone (PTH)
|
Unknown
|
Decrease
|
|
Estrogens
|
Unknown
|
Decrease
|
Neural
factors controlling hair
growth
The role of neural factors on hair growth is affirmed by the
fact that the hair follicle is richly innervated. A constant remodeling
of these innervations takes place during the follicular growth
cycle. Transplantation studies of skin in rats and of hair follicle
relocations in human scalps have shown that cycling process continues
despite the temporary denervation. Follicles have also been seen
to complete part of the growth cycle in organ culture. An intact
neural system is not therefore necessary for hair cycling and
it is not critically dependent on neural influences. However,
a direct or indirect regulating influence of the nerves on hair
growth cannot be ruled out.
Observations have shown that neurotransmitters and neuropeptides
play a role in hair cycle control. It has been seen that stimulation
of the neuropeptides and neurotransmitters can alter the proliferation
and differentiation keratinocytes. When substance P was administered
to mice, it induced development of anagen and catagen depending
on the stage of the hair growth cycle when the substance P is
applied.
In the early anagen stage, the epithelial stem cell region
of the hair follicles express beta – adrenoreceptors. It
has been observed that the beta – adrenoreceptors agonist
isoprotenerol causes cycling progression from anagen stage 3 to
4 in skin organ culture of mice and norepinophrine depletion induces
premature anagen onset. This proves the relevance of neuropeptides
and neurotransmitters in hair cycle control.
Trauma or toxic degeneration of the peripheral nerves can also
lead to loss of hair follicles. When capsacin is administered
to rat skin, it causes a sensory denervation, which leads to a
retardation of hair shaft thickness. On the other hand, after
major thoracic
surgery, an increase in hair growth is often observed because
of peripheral nerve damage - possibly because of posttraumatic
sympathetic hyperinnervation. Another phenomenon is
hair loss due to severe psycho emotional stress.
The nervous system also has an influence on the immunology of
the skin indirectly affecting hair growth. The neuropeptide substance
P in perifollicular nerve endings has been observed to produce
mast cell degranulation in mice skin organ culture. Murine hair
cycling has been found to fluctuate when the mast cell to nerve
fiber contacts were increased or decreased. Besides, both anagen
and catagen development in mice seem to be dependent on mast cell
degranulation. These observations lead to the premise that hair
growth may well be affected by neuropeptides released
by the sensory nerve fibers that act on mast cells and in turn
the mast cel degranulation response controls hair growth cycling.
There is also a neuroendocrine influence on hair growth. Neurohormones
such as prolactin, melatonin and ACTH play a role in the hair
growth cycle. The pilosebaceous unit itself can produce neurohormones
in different degrees over the different stages of hair cycling.
Assays with skin organ cultures have indicated that neurotrophins
and their receptors play a definite role in hair follicle morphogenesis
and cycling. Hair follicles produce neurotrophins NGF, neurotensin—3,
NT – 4 and brain derived neurotrophic factor (BDNF). The
follicle cycling is also affected by these neurotrophines.
One can sum up the influence neurotrophins have over hair cycle
control in the following way:
- Neurotrophins are expressed by the cells in the bulge region
of the hair follicle. They stimulate the cognate receptors
in the hair follicle epithelium and mesenchyme.
- Production of neurotrophins
depends on the hair cycle. This in turn influences hair cycling.
- Follicle
or glia - derived neurotrophins affect the mast cells or macrophages
which are essential immunological elements influencing
hair
cycling.
All these factors taken together definitely establish a connection
between the nervous system and hair follicle cycling.
Role
of the immune system in regulating hair
growth
Experiments have demonstrated that during synchronized cycling
in rats, there is a distinct change in the number, location and
activation of mast cells, macrophages, Langerhans cells and T
cells. This establishes a relation between the immune
system
and hair growth cycle. ICAM-1, an adhesion molecule, which is
expressed by some follicle compartments leads to the accumulation
of perifollicular macrophages. This also suggests that changes
in the number, location or activity of these macrophages affect
hair cycle control.
When the hair follicle bulb or the bulge isthmus region is attacked
by cell infiltration, it leads to severe forms of hair loss or
transformation from terminal hair to vellus hair. These components
of the skin immune system can therefore be said to control hair
growth. It has been proved that immunosuppressive drugs like cyclosporine,
FK506 and glucocorticosteroids control hair growth. Some of the
hair growth regulating agents also have properties that influence
the immune system. While these drugs act first and foremost directly
on the hair follicle keratinocytes, they may also promote hair
growth through altering the immune cells in the skin.
Investigations are still ongoing on the actual influence of
the immune system on hair cycle control - especially the role
of perifollicular
mast cells and macrophages. Perifollicular mast cells are responsible
for the remodeling of the skin tissue during hair cycling. Studies
on mouse skin have indicated that mast cells degranulate during
anagen to catagen as well as the telogen to anagen transformation
stage. So blocking mast cell degranulation by inhibitors can block
anagen and catagen development in hair follicles. While mast
cell chemical secretions can induce catagen and anagen stages
in mice, administration
of
histamine or serotonin receptors can also slow down anagen development
in vivo.
Similarly, activated macrophages in the vicinity of the hair
are found in the anagen to catagen stage in rats. Westgate postulated
that during the end of anagen IV stage, there is an attack of
macrophages on MHC class 1 negative keratinocytes of the hair
bulbs. This it is believed triggers the onset of catagen. This
theory however still needs to be substantiated by more convincing
evidence. It is also notable that IL-1, TNF-alpha and FGF5,
which
are needed to induce catagen are all secreted by macrophages,
suggesting a relation between the two.
Other
factors that regulate hair
growth
Intrinsic factors in the skin may affect hair growth. Increased
vascularity, with application of Vascular Endothelial Growth Factor
(VEGF) for example, promotes hair growth in certain stages of
anagen. Sometimes the resting hair follicles near the site of
a mechanical wound enter into anagen and this might be due in
part to an increase in VEGF production in the skin as part of
wound healing.
Irradiation affects a growing hair follicle, but has much less
effect on resting follicles. Cell division of matrix cells
is stopped
by irradiation and the follicle enters a catagen stage,
though no club hair is produced. Lower radiation doses damage
the matrix cells and cause temporary epilation. If the dermal
papilla
is
damaged, as it can be with high radiation doses, it causes permanent
epilation.
Apart from the effects of neurohormones on hair cycling, it
has been found that estrogen restricts follicle activity in rats,
but sex hormones can activate hair growth in humans. Further investigation
is required for a full understanding of this phenomenon
and why there might be differences in hair growth repsone to estrogens
in rodents compared to humans.
Several other factors also
contribute to hair growth cycle induction or retardation. Plucking
of telogen club hairs promotes hair growth
in the plucked follicle. Irritant chemical stimulus may also
induce hair growth possibly through promitng a mild skin injury.
Use of some chemicals affects hair growth. Chemicals like methyl
cholanthrene
result
in resting
hairs
to
fall out in
mice,
although
it does not affect hairs in the anagen stage. In short, there
is a lot more that we don't know about hair growth regulation
than we do know and there is much more to learn!
Hair
follicle growth cycle regulation references
- Stenn KS, Paus R. Controls
of hair follicle cycling.
Physiol Rev. 2001 Jan;81(1):449-494.
- Foitzik K, Lindner G, Mueller-Roever
S, Maurer M, Botchkareva N, Botchkarev V, Handjiski B, Metz
M, Hibino T, Soma T, Dotto GP, Paus R. Control of murine hair
follicle regression (catagen) by TGF-beta1 in vivo. FASEB
J. 2000 Apr;14(5):752-60.
- Sato N, Leopold PL, Crystal RG. Induction
of the hair growth phase in postnatal mice by localized transient
expression of Sonic hedgehog. J Clin Invest. 1999 Oct;104(7):855-64.
- Stenn KS, Combates NJ, Eilertsen KJ,
Gordon JS, Pardinas JR, Parimoo S, Prouty SM. Hair follicle
growth controls. Dermatol Clin. 1996 Oct;14(4):543-58.
- Stenn KS, Prouty SM, Seiberg M. Molecules
of the cycling hair follicle--a tabulated review. J Dermatol
Sci. 1994 Jul;7 Suppl:S109-24.
- Messenger AG. The control of hair growth:
an overview. J Invest Dermatol. 1993 Jul;101(1 Suppl):4S-9S.
- Paus R, Stenn KS, Link RE. Telogen skin
contains an inhibitor of hair growth. Br J Dermatol. 1990
Jun;122(6):777-84.
- Ebling FJ. The hair cycle and its regulation.
Clin Dermatol. 1988 Oct-Dec;6(4):67-73.
- Bertolino AP. Hair growth
regulation: a molecular biologic approach. J Invest Dermatol.
1991 May;96(5):82S-83S.
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