ARTICLE
Auteur(s) : Jung-Il
Kang1, Sang-Cheol Kim1, Jae-Hee
Hyun1, Ji-Hoon Kang1, Doek-Bae
Park1, Young-Jae Lee2, Eun-Sook
Yoo1, Hee-Kyoung
Kang1
1Department of Medicine, College
of Medicine, Cheju National University, 66 Jejudaehakno,
Jeju 690-756, South Korea
2Department of Veterinary Medicine, College
of Veterinary medicine, Cheju National University,
66 Jejudaehakno, Jeju 690-756, South Korea
accepté le 30 Septembre 2008
Alopecia is a distressing condition for an increasing number of
men and women and is characterized by a decrease in anagen hair
follicles, an increase of vellus-like hair, and miniaturization of
the hair follicles [1]. Androgenetic alopecia (AGA), which is the
most common type of alopecia, is a common problem in men over the
age of 40. However, the underlying causes of baldness are poorly
understood, and only two FDA-approved drugs (minoxidil and
finasteride) have been available for treatment of AGA for nearly 50
years [2, 3].
Hair follicle morphogenesis is governed through interaction
between epithelial and mesenchymal cells, which eventually leads to
the formation of mature follicles [4]. The cyclic change of the
hair follicle, which occurs over the entire lifetime of a mammal,
involves a growth phase (anagen), an involution phase (catagen) and
a resting phase (telogen) [5]. Previous studies have demonstrated
that multiple factors are involved in the regulation of hair
follicle morphogenesis and the hair cycle, and it has been shown
that hair growth is regulated by both an increase of anagen
maintaining factors and a decrease of cytokines that promote
apoptosis during the hair cycle [4, 6-8]. Specifically, the
development of AGA is predominantly androgen-dependent and
modulated via the testosterone metabolism [9]. Dihydrotestosterone
(DHT), a metabolite of circulating testosterone, is produced
systemically by intrafollicular conversion of testosterone to DHT
via 5α-reductase within the hair follicle of genetically
predisposed men [10]. DHT is an effector hormone that leads to a
continuous shortening of the anagen phase in favor of longer
telogen phases, which eventually leads to miniaturization of the
hair follicle [10]. According to recent reports, androgens, such as
DHT, which stimulate the synthesis of transforming growth factor-β
(TGF-β) in dermal papilla cells, are responsible for the inhibition
of androgen-induced epithelial cell growth [11]. The dermal
papilla, which is the mesenchymal component, is located at the
deepest end of the hair follicle and believed to play an essential
role in the induction of anagen hair follicles and the maintenance
of hair growth [12, 13].
To develop new therapies to enhance hair growth, we screened
extracts of plants that have traditionally been used in oriental
medicine and reported to inhibit the androgen receptor or activate
the estrogen receptor. It has been reported that plants in the
Schisandraceae family exert anti-inflammatory [14-16],
anti-oxidative [17], anti-carcinogenic [18-20], and anti-allergic
effects [21]. Moreover, these plants exert vasodilatory effects via
activation of estrogen receptors [17]. Even though several studies
have been conducted to evaluate Schisandraceae, few have evaluated
its side effects. However, neurotic vascular reactions have been
reported in patients with stomach and duodenal ulcers who were
treated with Schisandra chinensis [22]. Schisandra nigra is a
member of Schisandraceae that has been used in traditional medicine
to increase cardiac function. In Korea, the distribution of S.
nigra is limited to the mid-slope of the Halla mountain on Jeju
island. The pharmacological activity of S. nigra has not yet been
reported, although it has been found to contain various
constituents, such as schizandronic acid, β-sitosterol,
schisandrolic acid, oplodiol, schizandronol,
(+)-catechin-7-β-D-glucopyranoside, β-sitosteryl glucoside,
androsin and schizandriside [23, 24]. Pharmacological studies of
constituents isolated from other plants have shown that
schisandrolic acid exerts cytotoxic effects [25], whereas
schizandriside [26] and oplodiol [27] possess antibacterial
activity and androsin exerts anti-asthmatic activity [28].
In this study, we demonstrated that the extract of S. nigra
promoted hair growth both in vitro and in vivo, and that this
effect occurred via inhibition of the expression of TGF-β2 in the
bulb matrix region and the increased proliferation of dermal
papilla cells.
Materials and methods
Preparation of Schisandra nigra extract
Fresh fruit produced by Schisandra nigra were collected during
September, 2005 on Jeju Island, South Korea. The fruit was washed
with distilled water and then 1 kilogram of S. nigra was extracted
with 3 liters of 85% ethanol (EtOH) at room temperature for 3 days.
The EtOH extract was then concentrated using a vacuum evaporator.
The weight of the resulting residue was determined (67.65 g),
and it was then dissolved in dimethyl sulfoxide (DMSO) (Sigma, Mo,
USA) for subsequent treatment.
Animals
Male Wistar rats (3 weeks of age) and female C57BL/6 mice (6 weeks
of age) were purchased from Japan SLC (Hamamatsu, Japan) and
provided with a standard laboratory diet and water ad libitum. All
animals were cared for by using protocols (20070002) approved by
the Institutional Animal Care and Use Committee (IACUC) of the
Cheju National University.
Cell Culture
Rat vibrissa immortalized dermal papilla cell line [29] was donated
by the Skin Research Institute, Amore Pacific Corporation R&D
Center, South Korea. Dermal papilla cells were cultured in DMEM
(Hyclone Inc, USA) supplemented with 10% fetal bovine serum (Gibco
BRL, NY, USA) and penicillin/streptomycin (100 unit/mL and
100 μg/mL, respectively) at 37 °C in a humidified
atmosphere under 5% CO2.
Isolation and culture of rat vibrissa follicles
Isolation of rat vibrissa follicles was performed as described
previously [30, 31]. Briefly, rat vibrissa follicles were harvested
from male Wistar rats that were 23 days old. To accomplish this,
the rats were sacrificed under diethylether. Next, both the left
and right mystacial pads were removed from the rats and placed in a
1:1 (vol/vol) solution of Earle’s balanced salts solution (EBSS,
Sigma, MO, USA) and phosphate buffered saline (PBS, Sigma, MO, USA)
that contained 100 unit/mL of penicillin and 100 μg/mL of
streptomycin. Anagen vibrissa follicles were then carefully
dissected under a stereomicroscope (Olympus, Japan), with
considerable care being taken to remove the surrounding connective
tissue without damaging the vibrissa follicle. Using this method we
were able to routinely isolate more than 40 follicles from each
animal. The isolated follicles were then placed in separate wells
in 24-well plates that contained 500 μL of Williams medium E
(Gibco Inc, NY, USA) supplemented with 2 mM L-glutamine (Gibco
Inc, NY, USA), 10 μg/mL insulin (Sigma, MO, USA), 50 nM
hydrocortisone (Sigma, MO, USA), 100 unit/mL penicillin and
100 μg/mL streptomycin at 37 °C and cultivated in an
atmosphere comprised of 5% CO2 and 95% air. The isolated follicles
were then treated with 5, 10, 20 and 50 μg/mL of the EtOH
extract of S. nigra. Minoxidil sulfate (Sigma, MO, USA) was used as
a positive control in the culture systems [32]. The culture medium
was changed every 3 days and photographs of the cultured rat
vibrissa follicles were taken using a stereomicroscope for 3 weeks.
The length of the hair follicles was measured using a DP controller
(Olympus, Japan).
Hair growth activity in vivo
Anagen was induced on the back skin of C57BL/6 mice that were in
the telogen phase of the cycle by depilation, as described
previously [33]. Briefly, 6 week old female C57BL/6 mice were
allowed to adapt to their new environment for one week. The anagen
was then induced in the back skin of the seven week old female
C57BL/6 mice by depilation, which led to synchronized development
of anagen hair follicles. From the following day (day 1),
0.2 mL of 20 μg/mL S. nigra extract in 50% ethanol was
topically applied on every second day for 15 days. The back skin of
the mice was then observed and photographed at 1, 8, 12 and 15 days
after depilation.
MTT Assay
The proliferation of dermal papilla cells was evaluated by
measuring the metabolic activity using a
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
assay [34]. The MTT assays were performed as follows: dermal
papilla (1.0 × 104 cells/mL) were treated for 4
days with 0.1, 1, 5, 10, 20 and 50 μg/mL of the S. nigra
extract. After incubation, 0.1 mg (50 μL of a
2 mg/mL solution) of MTT (Sigma, MO, USA) was added to each
well, and the cells were then incubated at 37 °C for 4 h.
Next, the plates were centrifuged at 1000 rpm for 5 min at
room temperature and the media was then carefully aspirated.
150 μL of dimethylsulfoxide was then added to each well to
dissolve the formazan crystals and the absorbance of the plates at
540 nm was then read immediately on a microplate reader
(Amersham Pharmacia Biotech., USA). All experiments were performed
three times and the mean absorbance values were calculated. The
results are expressed as the percentage reduction in the absorbance
caused by treatment with crude extract compared to that of the
untreated controls.
Immunohistochemistry
For immunohistochemistry, vibrissa follicles were collected from
each group on days 0 and 7 of treatment. The vibrissa follicles
were fixed in 4% paraformaldehyde (Sigma-Aldrich, USA), and the
tissues were then dehydrated and embedded in paraffin.
Immunohistochemistry was then performed according to the
manufacturer’s instructions (Santa Cruz Biotechnology, CA, USA).
The following primary antibodies were used at the indicated
concentrations: PCNA and TGF-β2 (1:200; Santa Cruz Biotechnology,
Santa Cruz, CA, USA). In addition, the relevant goat secondary
antibodies (1:200; Santa Cruz Biotechnology, CA, USA) were used for
detection of the primary antibodies.
Statistical analyses
The hair growth data are expressed as the mean of the follicle
lengths ± the standard errors (SEM) of at least three independent
experiments performed in triplicate. The Student’s t-test was used
to determine the statistical significance (P-value < 0.05) of
the differences between the values for the various experimental and
control groups.
Results
The effects of S. nigra extract on rat vibrissa
follicle elongation
To determine if S. nigra induced hair growth, we examined the
activity of the S. nigra extract using an organ culture of rat
vibrissa follicle. When rat vibrissa follicles were treated with 5,
10, 20 and 50 μg/mL of S. nigra extract for 3 weeks, the
hair-fiber length of the vibrissa follicles were significantly
increased in a time dependent manner with respect to the control
(figure 1). In
particular, in the vibrissa follicle that was treated with
20 μg/mL of the S. nigra extract for 21 day, the vibrissa
follicles were 122% longer (P < 0.05) than those in the control
group (figure
2). Although the S. nigra extract had beneficial effects on
hair growth, no effects were seen when a concentration of
50 μg/mL was used. Nevertheless, these results indicate that
S. nigra extract is capable of promoting hair growth.
The effects of S. nigra extract on anagen induction
in C57BL/6 mice
In order to measure the hair growth activity in vivo, we examined
the effects of the S. nigra extract on C57BL/6 mice. After being
shaved, the skin color was observed to be pink. The hair on the
back skin that was treated with 20 μg/mL of S. nigra extract
uniformly grew back on the 8th and 12th day, whereas the hair that
grew back on the back skin of the control group was clearly less
pigmented. However, on 15th day, the back skin was in anagen phase
in all of the mice (figure 3). Overall, these
results indicate that the S. nigra extract induced early
telogen-to-anangen conversion of hair follicles in the C57BL/6
mice.
The effects of S. nigra extract on cell proliferation
of hair follicles
To evaluate effect of S. nigra on cell proliferation of hair
follicles, proliferation of dermal papilla cells and the expression
of PCNA were examined.
Immortalized rat vibrissa dermal papilla cells were treated with
various concentrations of S. nigra extract and the mitogenic effect
on the dermal papilla cells was examined. Treatment of the dermal
papilla cells with 10 μg/mL or less of S. nigra extract
increased the proliferation of dermal papilla cells, however, the
proliferation of these cells decreased at concentrations higher
than 20 μg/mL (figure 4). The
proliferation of dermal papilla cells that were treated with 0.01,
0.1 or 1 μg/mL of S. nigra extract was similar to that of
cells that were treated with 1 or 10 μM minoxidil sulfate.
These results suggest that the hair growth promoting effect of S.
nigra extract may be mediated through a mitogenic effect on the
dermal papilla cells.
The isolated rat vibrissa follicles were treated with the S.
nigra extract and then examined for activation of PCNA (figure 5). In the anagen
vibrissa follicles (0 day), the expression of PCNA was positively
stained in the bulb region, whereas the 7 day-cultured vibrissa
follicles, which were expected to be in the anagen-catagen
transition phase were negatively stained, whereas the vibrissa
follicles treated with 20 μg/mL of S. nigra extract for 7 days
were positively stained in the bulb regions. In addition, the bulb
regions of the vibrissa follicles that were treated with 10 μM
of minoxidil sulfate for 7 days were positive for PCNA. These
results indicate that the cells in the bulb regions of follicles
treated with the S. nigra extract or minoxidil sulfate were induced
to grow (figure
5).
The effects of S. nigra extract on TGF-β2
expression in rat vibrissa follicles
In order to investigate the mechanisms by which S. nigra induces
hair growth, the expression of TGF-β2, a regulator of catagen
induction, was examined in the cultured vibrissa follicles (figure 6). On day 0,
most of the cells in the anagen follicles were negative for TGF-β2
in the bulb region. However, after 7 days, the cultured vibrissa
follicles, which were expected to be in the anagen-catagen
transition phase, were positive for TGF-β2, whereas the vibrissa
follicles treated with 20 μg/mL of the S. nigra extractfor 7
days were negative for TGF-β2 in the bulb region. Furthermore, the
bulb region of the vibrissa follicle treated with 10 μM of
minoxidil sulfate for 7 days was negative for TGF-β2. These results
indicate that treatment with S. nigra extract might decrease the
expression of TGF-β2, thereby preventing apoptosis from occurring
in the bulb region (figure 6).
Discussion
In this study the hair growth promoting effects of S. nigra in
vitro and in vivo were investigated. To the best of our knowledge,
this study is first to demonstrate that the extract of S. nigra has
the potential to promote hair growth via down regulation of TGF-β2
and the proliferation of dermal papilla.
The results of this study showed that the S. nigra extract
increased hair-fiber length in cultured rat vibrissa follicles.
Specifically, 20 μg/mL of S. nigra extract was found to induce
a greater increase in hair-fiber length than minoxidil sulfate. Use
of the organ culture methods to evaluate hair follicle growth is
thought to be correlated with in vivo systems because the extent of
hair growth can be observed as the sum of the function of each cell
[30]. The hair growth stimulating in vitro effect of S. nigra
extract was also observed in vivo using C57BL/6 mice.
To investigate the effect of S. nigra on cell growth in the hair
follicles, we examined the proliferation of dermal papilla cells
and the expression of PCNA. The S. nigra extract was found to
increase the growth of dermal papilla cells and the expression of
PCNA in the bulb region of the 7 day-cultured follicles. Modulation
of the balance of proliferation and apoptosis in the dermal papilla
may be a key strategy for the control of hair growth and regression
[35], and PCNA immunoreactivity in keratinocyte acts as an index of
cell proliferation [36]. Taken together, the results of this study
indicated that that the hair growth induced by S. nigra extract may
be mediated through mitogenic effects that occur in the dermal
papilla region.
The mechanism by which S. nigra induced hair growth was
evaluated by measuring the expression of TGF-β2 in follicles
treated with S. nigra extract. The results indicate that treatment
with S. nigra extract decreased the expression of TGF-β2 in the
bulb region of 7 day-cultured follicles. Recently, several growth
factors have been found to play important regulatory roles in the
growth of hair [37-40], and TGF-β has been shown to play a critical
role in the growth of hair follicles as well as their morphogenesis
[41, 42]. Moreover, TGF-β is believed to inhibit hair growth and
contribute to the promotion of the regression phase of the hair
cycle in human hair follicles [43, 44]. Hair follicles treated with
TGF-β2 have been found to exhibit decreased hair growth and
categen-like morphology [44], and the localization of the TGF-β
isoform in hair follicles has also been observed [45]. TGF-β1 and
TGF-β3 were strongly detected in the hair cuticle, hair cortex and
CTS of the anagen hair follicle [45]. Conversely, when the
anagen-catagen transition was evaluated, the expression of TGF-β2
markedly increased in bulb matrix cells [45]. In addition, caspase
has been found to be activated in the bulb matrix region when hair
follicles were cultivated in the presence TGF-β2 [45], and
procyanidin B-3 obtained from barley has been shown to stimulate
hair growth by counteracting the inhibitory effects caused by
TGF-β1 [46]. The TGF-β receptors are found in C57BL/6 mice [41],
and the presence of TGF-β1 is sufficient to induce apoptosis in
keratinocytes [47]. TGF-β2 and TUNEL positive cells were found in a
similar area of the catagen hair follicle, which indicates that
TGF-β2 expression in the bulb region may be associated with catagen
induction [44, 45]. Moreover, the results of another study suggest
that TGF-β2 contributes to a decrease in the length of the hair
cycle via activation of the caspase network [48]. The results of
the present study indicated that the extract of S. nigra may
decrease the expression of TGF-β2 in the bulb region (figure 6), which would in
turn prevent apoptosis and promote hair growth in vibrissa hair
follicles and the back skin of C57BL/6 mice.
Overall, the results of this study demonstrated that S. nigra is
capable of promoting hair growth in vitro and in vivo via
down-regulation of TGF-β2 and the proliferation of dermal papilla.
However, the mechanism by which S. nigra promotes these effects
remains to be elucidated; therefore, further studies should be
conducted to evaluate its mechanism of action.
Acknowledgements
This research was financially supported by the Ministry of
Education, Science and Technology (MEST) and the Korea Industrial
Technology Foundation (KOTEF) through the Human Resource Training
Project for Regional Innovation.
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