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Review
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HAIR LOSS AND REGENERATION PERFORMED ON
ANIMAL MODELS
MEDA SANDRA ORASAN1, IULIA IOANA ROMAN2, ANDREI CONEAC3,
ADRIANA MURESAN2, REMUS IOAN ORASAN2
1Department of Physiopathology, Iuliu Hatieganu University of Medicine and
Pharmacy, Cluj-Napoca, Romania
2Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania
3Department of Histology, Iuliu Hatieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania
Abstract
Research in the eld of reversal hair loss remains a challenging subject.
As Minoxidil 2% or 5% and Finasteride are so far the only FDA approved topical
treatments for inducing hair regrowth, research is necessary in order to improve
therapeutical approach in alopecia. In vitro studies have focused on cultures of a cell
type - dermal papilla or organ culture of isolated cell follicles. In vivo research on
this topic was performed on mice, rats, hamsters, rabbits, sheep and monkeys, taking
into consideration the advantages and disadvantages of each animal model and the
depilation options. Further studies are required not only to compare the efciency of
different therapies but more importantly to establish their long term safety.
Keywords: hair regrowth, animal models, research in vivo, alopecia
for signaling or communication and sometimes provides
defensive functions [11].
Hair can also modify its color over the time, both in
animals and humans: from vellus hairs in babies (uncolored,
soft hair) into nal hair in adult males (colored beard, thick
and strong hair) [12]. Along the aging process it loses its
pigment and becomes white.
Although human hair has lost its main
thermoregulatory function, hair growing on the head has an
important role in heat insulation and cooling by evaporating
sweat from soaked hair [13,14]. It also protects the scalp
against ultra-violet radiation by acting like a sunscreen
[15,16].
Structure of hair
Hair is deriving from the ectoderm of the skin and
represents an accessory structure of the integument along
with the sebaceous glands, sweat glands and nails [8,12].
The word “hair” usually refers to two distinct structures:
the hair follicle (beneath the skin) and the shaft of the
hair (hard lamentous part that extends above the skin
surface). In a cross section evaluation the shaft consists of
The physical appearance of both males and females
is under society pressure, due to the interest in the general
aspect of the individual regarding body shape, hair, make-
up and clothing [1-5].
Hair brings an important contribution to the outlook
of human body [6,7] playing an interesting part in social and
sexual communication, as many hair loss studies show [8]
.
This idea is also supported by the fact in some
cultures young women are asked to cover their hair,
which indirectly suggests its role in the overall beauty and
attraction.
Functions of hair
Hair represents a dening characteristic of
mammals, with an important thermoregulatory function.
Also it has camouage purposes, hair follicles being able
to modify their type and density during seasonal coat
changes [9]. Besides offering protection, hair also has a
sensory function, extending the sense of touch that occurs
at skin level [10]. In animals, the hair/fur is often used
DOI: 10.15386/cjmed-583
Manuscript received: 21.09.2015
Accepted: 05.10.2015
Address for correspondence: andrei.coneac@gmail.com
Dermatology
Clujul Medical
three layers, starting from the outside: the cuticle (having
several layers of at, thin cells, overlapping one another),
the cortex (containing the keratin bundles in rod-like cell
structures) and the medulla (a disorganized and open area
at the ber’s center) [17,18].
On the other hand, in the dermis, we nd the bulb,
which maintains stem cells that not only re-grow the hair
after it falls out, but are also recruited to repair skin after a
wound [9].
The hair follicle pigmentary unit provides the hair
shaft melanin components, due to precise interactions
between follicular melanocytes, keratinocytes and
specialized dermal papilla broblasts (also involved
in wound healing) [19,20]. The dermal papilla has an
important role in hair formation, growth and cycling [21].
The blood vessels from the dermal papillae nourish all hair
follicles and offer nutrients and oxygen to epidermal cells
in the lower layers.
In the human skin, the dermal papillae are small
extensions of the dermis into the epidermis and at the
surface of the hands and feet, they appear as epidermal or
papillary ridges, also called ngerprints [22].
Biology of the hair loss and hair regrowth
Human hair is different from hair grown by
mammals, due to the unsynchronized growth cycles. Even
if there is a certain seasonal co-ordination, each human
hair follicle works independently [23,24,25]. This mosaic
human pattern consists of hair in different stages: 90%
anagen (growth phase), 1-2% catagen (regression phase)
and 8-9% telogen (resting phase). [26,27]. The cyclic
changes from anagen to telogen via catagen involve rapid
remodelling of both the epithelial and dermal components
of hair follicles [28,29]. In animals, as in humans, the hair
cycle is inuenced by stimulatory and inhibitory factors,
such as hormones, growth factors, cytokines, neuropeptides
and pharmaceutical products [26,30,31].
The dermal papilla, as the main mesenchymal
component, induces the new hair follicles formation and
maintains hair growth [32]. In telogen phase the old hair
is lost, but the follicle will be regenerated in early anagen,
when a new hair grows up. In order for this to happen, the
dermal papilla cells support an increased cell division and
growth rate that also require a good supply of nutrients and
a toxin-free environment for the growing cells. If these
requirements are not fullled the follicles will remain in
the telogen phase [33].
Two factors usually determine terminal hair
miniaturization leading to hair loss. The rst is the
shortening of the anagen, within an abnormal hair cycle
and the anagen: telogen rate shifting from 6:1 to 2:1. The
consequence of this process would be a shortening of hairs,
shaft loss and an increased number of hairs in telogen phase.
The second factor with a negative impact on hair growth is
the small size dermal papilla or the hair matrix leading
to hair modication both in diameter and aspect. Final hair
(thick and pigmented) turns into vellus (thin and white).
Scientists have also discovered that in hair loss, the scalp
suffers of vasoconstriction and hypoxia [34,35,36].
The sensitive response to androgen is the second
feature characterizing human hair in contrast to the hair
grown by mammals. An excess of androgens generates hair
miniaturization and thinning, followed by hair fall and loss
of pigment, mostly in the vertex and the crown-frontal area
of the scalp [37,38].
There are some characteristics of the hair depending
on localization in a specic site of the body: beard, axially
and pubic hair react differently than hair from the scalp,
as they are androgen-sensitive [12]. The metabolization of
the testosterone into 5-alpha-dihydrotestosterone has also
been of great research interest. Results show that good
metabolization limits the length of hair growth (beard) and
the 5 alpha-reductase deciency produces strong thick hair
(axilla and pubic area) [27,39,40,41,42].
On the other hand, androgens act on the hair via the
dermal papilla and stimulate the production of terminal hairs
after puberty, but have no hair growth effect on eyelashes
and the occipital area [43,44]. Androgens seem to alter the
production of regulatory factors (soluble paracrine factors
and extracellular matrix components) by the dermal papilla
cells [21].
Consequences of hair loss
Although a natural part of the aging process, hair
loss represents a great concern for the patient, who suffers
from anxiety and distress more severely than expected
[45]. Several studies already showed that this common
dermatological condition generates adverse psychosocial
sequelae [46]. Cash et al found that the psychological
effects of hair loss on women are far more severe than
in male subjects. Surveys have shown that around 40%
of women with alopecia have had marital problems and
around 63% claimed to have career related problems [47].
Hair loss is a stressful experience for both sexes, but
substantially more distressing for women, as they do not
accept the disease, neither do they cope with it as easily as
men [48]. Stress functions as a cause and risk factor in the
development of the disease, but it is also a consequence
of hair loss. Alopecia determines a poor quality of life by
the physical, psychological and social consequences it
produces. It causes low self-esteem, depression and distorts
social perception and psychosocial functioning [49,50].
A large variety of over the counter products claim
to treat hair loss pathology. This multibillion dollar,
worldwide market of hair tonics, hair balms, hair masks,
shampoos, leave in conditioners, topical solutions or foams
function as potential anti-hair loss agents [51]. However, in
most of the cases, clinical studies do not prove how these
doubtful hair growth-promoters exert their expected effects
of ceasing hair loss and enhancing hair regrowth [51].
As a consequence, clinically speaking, there is an
increased number of patients with “great expectations”
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who, encounter plenty of disappointments after the
treatment [52,53].
Evaluation of hair loss and hair regrowth
Unfortunately, researchers do not have a
standardized method to assess hair regrowth in vivo.
Possible tools include scales of measuring hair regrowth
based on percentage evaluations that can be performed
with the naked eye (visualization and photographs of the
area of interest) or by trichoscopy [49]. These qualitative
assessments are limited in number, therefore, new, accurate
and minimally invasive procedures are still needed.
To explore the efciency of a topic substance in
inducing hair growth, in vivo, researchers usually analyze
the hair growing pattern in animal groups treated with
different substances, compared to control by using the
macroscopic aspect. The skin of the animals, usually the
dorsal part, is observed and photographed either every 3
days or at specic time intervals (day 1, 7, 14 and 21 after
depilation) in order to notice the start of hair regrowth
period and the hair regrowth pattern. There are several hair
regrowth potential scores, but one easy to use was described
by Matsuda et al: 0 = no hair growth, 1 = less than 20% of
hair growth, 2=20-39% of hair growth, 3=40-59%of hair
regrowth, 4=60-79% of hair regrowth, 5=80-100% of hair
regrowth [54]. Researchers also use self-designed scales
of hair regrowth, such as: Type 4 (high hair density, full,
thick fur), Type 3 (moderate hair density with no visible
skin area), Type 2 (low hair density, with the visualization
of the skin), Type 1 (uneven hair growth on the test area,
skin easily seen) [55].
Trichoscopy is performed with a hand held device
called dermatoscope, with polarized light to magnify and
allow inspection of the skin. A decrease of hair diameter
up to ten times or diameter variations can be detected by
trichoscopy, so a correct hair regrowth evaluation can be
performed.
As far as quantitative methods are concerned, an
area of 1 cm² of skin with regrown hair is cut and weighed
with an analytical balance for hair weight determination
[56].
To further investigate the hair growth promoting
effect of a certain substance, the histopathological
examination offers a precise and necessary evaluation tool
for hair regrowth. Usually, at the end of the treatment period,
the rats are sacriced and a skin biopsy is isolated in order
to examine the histological features. The skin thickness
and hair follicles localization in the dermis/subcutis can
be evaluated by microscopic photograph (magnication
x400). Taking into consideration the existent knowledge
about hair cyclicity, the anagen induction is calculated with
the formula: (number of follicles in subcutis)x100( number
of follicles in dermis). Previous microscopical studies
on animals showed an association of increasing skin
thickness, follicle count and macroscopic development of
skin pigmentation with anagen induction [26,31].
The hair growth cyclicity (anagen, catagen, and
telogen phases) can be used as a diagnosis tool for the
hair growth condition and also as a treatment assessment
method for the hair growth promoting agent.
Hair regrowth treatment
The insufcient insight into the basic mechanism
leading to alopecia together with therapies that failed to
cure it, determined scientists to developed large research
programs to overcome hair loss [57]. Despite the many
treatment alternatives that have been tested, hair loss
continues to remain a frequent dermatological condition.
Up to the present, pharmaceutical hair loss
management includes only two FDA approved hair loss
drugs: Finasteride and Minoxidil, both commonly used in
clinical practice [46,51,58].
The hair growing effect of Minoxidil has been
accidentally discovered, as this antihypertensive oral drug,
caused side effects such as increasing hair growth on the
scalp or even darkening the ne body hairs. The 2% topical
formulation was approved by the FDA in the 1990s for use
in treating androgenetic alopecia in men (for central/vertex
hair loss only) and in females as well (in female pattern hair
loss) [59]. The 5% formulation is allowed only for males
and the foam version is associated with 70% self-reported
improvement.
Minoxidil slows or stops hair loss and promotes
hair growth because it is a vasodilator that increases
the cutaneous blood ow to the scalp [60]. It is also a
potassium channel opener, causing hyperpolarization of
cell membranes, allowing more oxygen, blood and nutrients
to reach the follicle [61]. Minoxidil contains an N-oxide
group able to release NO, and besides being a vasodilator
[62], it also acts as a nitric oxide agonist. However, it has
no therapeutic action on the hormonal and genetic causes
of hair loss.
Minoxidil usual dosage is 1 mg per day, applied
topically, with slight massage on the affected area of the
scalp and no contact with water allowed for at least 4 hours
after application [63,64]. Minoxidil must be used as a
continuous support for the hair follicles, otherwise the hair
regrowth will ceases and hair loss will begin again in 30 to
60 days if Minoxidil treatment is stopped for more than 6
months [65]. Several studies have shown that the efcacy
of Minoxidil ranges from 20-40%, causing discontinuity of
treatment in the majority of patients [66].
Finasteride is considered a dihydrotestosteron-
suppressing 5 alfa-reductase inhibitor, recommended for
male use only, in the treatment of androgenetic alopecia. It
acts by decreasing the serum levels of dihydrotestosteron,
stopping hair fall (in 48% of the cases) and stimulating
hair regrowth (in 51% of the cases). Studies showed that 1
mg Finasterid oral treatment has a similar efcacy as daily
topical Minoxidil application on the scalp, but their efcacy
is seen after at least 4 months of daily usage [67,68]. These
two treatments can be combined in order to boost the hair
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Clujul Medical
follicles, but both treatments must be performed a-la-
longue, if not, the hair regrowth effect will cease. Adverse
reactions are rare, still sexual dysfunctions were reported in
4% of the cases [69,70].
Given the temporary efcacy of Finasteride and
Minoxidil and the limited number of treatments available
in alopecia, it is a challenge to discover new therapies
in order to prevent hair loss and enhance hair regrowth
[69,70]. Some substances diminish the physiopathological
processes that induce hair loss, but clinical studies in this
respect are lacking.
Arginin stimulates microcirculation, bringing in
essential nutrients for hair bulb growth.
Aminexil 1.5% diminishes the rate of hair loss as
it reduces the accelerated aging of the roots by ghting the
process of brosis. It also maintains the elasticity of the
tissue surrounding the hair root and prevents the stiffening
of collagen sheets, in order to fasten the hair root within the
scalp [52,53].
SP94 peptide is captured by the root and turned into
the hair constructive elements for building up the ber from
root to tip.
B5 and B6 Vitamins function as cellular nutrients
that nourish the hair roots and help generating beautiful,
shiny hair, that becomes thicker and stronger from within
[65].
Thermal Spring Water that contains anti-free
radical Selenium, enhances the therapeutic action of
Madecassoside, which inhibits the local micro-irritation,
preventing the spreading to the capillary bulb [65].
Low Level Laser Therapy (LLLT) provides
a promising treatment option for patients, this
photobiomodulation produces a shifting of the follicles
from telogen (resting phase) to anagen (active phase),
preventing premature catagen development (hair falling
phase) [71-73]. LLLT, through its low power coherent
monochromatic red light, produces vasodilation and
increases ATP production, also determining a modulation
of Reactive Oxygen Species (ROS) and inammatory
mediators [74-76].
Hair regrowth studies in vitro
Human hair follicles are not proper research material
due to ethical problems, invasive methods and limited
amount of follicles that can be extracted for testing [77,78].
Cotsarelis et al., discovered that bald areas have the same
number of stem cells as the normal scalp and also noticed
that hair follicles decrease in size, but do not disappear.
In alopecia, one of the major issues would represent the
activation of stem cells converting to progenitor cells in the
affected areas of the scalp [79].
Researchers insist in nding new natural and
chemical agents, which may convert stem cells into
progenitor cells and generate terminal hair [79,80].
In vivo models (experiments performed on natural
animals and genetically manipulated models) as well in
vitro research (cultures of a cell type - dermal papilla or
organ culture of isolated cell follicles ) have been used
successfully, to obtain the data that we now possess about
the function of the hair follicle in health or under disease
[81-86].
Scientists may choose one of the two types of
experimental studies taking into consideration the purpose
of the research, the advantages and disadvantages it offers.
Hair regrowth studies in vivo
Animal models
For a better understanding of the physiopathological
processes involved in hair loss and regeneration, animal
models have been used in hair research since 1950 [87].
In vivo research on hair loss and regrowth was
performed so far on mice, rats, hamsters, rabbits and sheep
in laboratory conditions [88,89,90,91]. Lately, the interest
in hair growth promoting agents has grown considerably
and in the attempt to discover an ideal therapy for alopecia,
new treatments have been studied even in stump-tailed
macaque [92]. Still, researchers must take into consideration
the differences between species regarding the follicular
function and limited androgen-sensitive models [93]. The
periodic intervals of rodent hair cycles, particularly the
duration of the anagen phase are much more consistent and
less susceptible to iatrogenic inuences [94].
The normal hair cycling, including growth waves
and hormonal control were studied on Wistar Bratislava
rats and mice [95]. The black mouse C57BL/6 was used
for the skin-free pigment and early visible pigmented tips
of new anagen regrowth [91,96]. The C3H mouse model
was the most widely reported for hair growth promotion,
even thought the increased hair density of the animal
and the wave pattern hair cycle progression presented
disadvantages [95,96,97]. Laser therapy applied in C3H
mouse, 20 second daily, 3 times per week, induced a much
longer growth phase, after only 2 weeks of treatment, with
most of the follicles from the tested area being in anagen
hair growth phase [98].
The androgen action upon the hair follicles has been
studied on spontaneous and genetically engineered nude
mutant mice. Immunodecient mice (with T and B cells
deciencies) were used as models for autoimmune disease
mechanisms and androgenetic alopecia studies [96]. Also,
by inhibiting the rejection of foreign skin, human skin
grafts were applied and even rat dermal papillas continued
to produce hair after reimplantation in vivo on a rat model
[99,100,101].
Recently scientists discovered that a certain
progenitor cell population in mice is analogous to the
human cells. These mature cells were tested by injection
on immunodecient mice animal model and the results
showed the development of new hair follicles and increased
hair regrowth [98].
The Mesocricetus auratus (Golden hamster)
was used for macroscopic assessment (hair density
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dermatoscopy analysis) and microscopic evaluation (hair
diameter analysis) as an animal model for hear regrowth
[102].
Since Minoxidil 2% is thought to be the gold
standard treatment for hair loss, scientists consider the
validation of Minoxidil treatment on an animal model
as being very important. Several studies have shown
that topical Minoxidil affects the normal hair cycle by
shortening telogen, causing premature entry of the resting
follicles into anagen phase which will lead to an increased
hair follicle size [103,104].
Housing conditions
Usually animals of either sex and weight were used
in the studies. They were acclimatized to the experimental
room at a temperature of 23 degrees Celsius, in controlled
humidity conditions with a 12:12 h light and dark cycle for at
least 7-14 days prior to the experiment. Usually, there was an
individual housing or maximum 2 animals per cage (to avoid
licking) with access to standard laboratory diet and water
ad libitum. Following the experiment they were euthanized
according to the current regulations. Some experiments were
performed in triplicate for accurate results
.
Depilation methods
Experimental designs may ask for the whole back or
body of the animal to be shaved, or there may be only some
specic areas to be denuded for testing.
In Dr. Mester’s study, before each successive
treatment, the skin was depilated by shaving, procedure
that may induce mechanic stimulation of hair growth, as
previously reported in the literature. An experiment done
on adult rats proved that after the fur was dyed and shaved,
concluded that the regrowing hairs on the rat skin formed a
system of linear loops, that were closely correlated with the
shaving process [74,75].
In order to avoid this effect, some scientists do
not shave the tested area of the animal model before each
daily therapy. It has been also proved that physical factors
inuence the hair regrowth process: temperature triggers
fast regrowth after shaving.
Depilation-induced hair cycle has a strict course: 9
days after depilation, the hair follicles enter the nal stage
of the growth cycle (anagen VI). Around day 17 the follicles
enter the regression stage (catagen) and around day 20 after
depilation, follicles get to the resting stage (telogen) [30].
Besides shaving, there are also other methods for
depilation, such as a raisin mixture or a hair removal cream
[91, 105].
Conclusion
As a conclusion, we tend to rene our knowledge
on human hair diseases and hair regrowth by using proper
animal models. Hair research provides further insights
into the physiopathological pathways, genetic and cell
biochemical mechanisms that could promise the cure of
hair loss.
Acknowledgments
This paper was published under the frame of the
European Social Found, Human Resources Development
Operational Programme 2007- 2013, project no.
POSDRU/159/1.5/S/138776.
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