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Abstract

Please cite this paper as: Polyamines and hair: a couple in search of perfection. Experimental Dermatology 2010; 19: 784–790. Abstract: Polyamines (spermidine, putrescine and spermine) are multifunctional cationic amines that are indispensable for cellular proliferation; of key significance in the growth of rapidly regenerating tissues and tumors. Given that the hair follicle (HF) is one of the most highly proliferative organs in mammalian biology, it is not surprising that polyamines are crucial to HF growth. Indeed, growing (anagen) HFs show the highest activity of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, while inhibition of ODC, using eflornithine, results in a decreased rate of excessive facial hair growth in vivo and inhibits human scalp hair growth in organ culture. In sheep, manipulation of dietary intake of polyamines also results in altered wool growth. Polyamine-containing nutraceuticals have therefore been proposed as promoters of human hair growth. Recent progress in polyamine research, coupled with renewed interest in the role of polyamines in skin biology, encourages one to revisit their potential roles in HF biology and highlights the need for a systematic evaluation of their mechanisms of action and clinical applications in the treatment of hair disorders. The present viewpoint essay outlines the key frontiers in polyamine-related hair research and defines the major open questions. Moreover, it argues that a renaissance in polyamine research in hair biology, well beyond the inhibition of ODC activity in hirsutism therapy, is important for the development of novel therapeutic strategies for the manipulation of human hair growth. Such targets could include the manipulation of polyamine biosynthesis and the topical administration of selected polyamines, such as spermidine.
Polyamines and hair: a couple in search of perfection
Yuval Ramot
1
, Marko Pietila¨
2
, Giammaria Giuliani
3
, Fabio Rinaldi
4
, Leena Alhonen
2
and Ralf Paus
5,6
1
Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
2
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio,
Kuopio, Finland;
3
Giuliani S.p.A, Milan, Italy;
4
International Hair Research Foundation (IHRF), Milan, Italy;
5
Department of Dermatology, University of Lu
¨beck, Lu
¨beck, Germany;
6
School of Translational Medicine, University of Manchester, Manchester, UK
Correspondence: Yuval Ramot, MD, MSc, Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel,
Tel.: +972 (0)2 677-7111, Fax: +972 (0)2 677-7299, e-mail: yramot@gmail.com
Accepted for publication 23 March 2010
Abstract: Polyamines (spermidine, putrescine and spermine) are
multifunctional cationic amines that are indispensable for cellular
proliferation; of key significance in the growth of rapidly
regenerating tissues and tumors. Given that the hair follicle (HF)
is one of the most highly proliferative organs in mammalian
biology, it is not surprising that polyamines are crucial to HF
growth. Indeed, growing (anagen) HFs show the highest activity
of ornithine decarboxylase (ODC), the rate-limiting enzyme of
polyamine biosynthesis, while inhibition of ODC, using
eflornithine, results in a decreased rate of excessive facial hair
growth in vivo and inhibits human scalp hair growth in organ
culture. In sheep, manipulation of dietary intake of polyamines
also results in altered wool growth. Polyamine-containing
nutraceuticals have therefore been proposed as promoters of
human hair growth. Recent progress in polyamine research,
coupled with renewed interest in the role of polyamines in skin
biology, encourages one to revisit their potential roles in HF
biology and highlights the need for a systematic evaluation of
their mechanisms of action and clinical applications in the
treatment of hair disorders. The present viewpoint essay outlines
the key frontiers in polyamine-related hair research and defines
the major open questions. Moreover, it argues that a renaissance
in polyamine research in hair biology, well beyond the inhibition
of ODC activity in hirsutism therapy, is important for the
development of novel therapeutic strategies for the manipulation
of human hair growth. Such targets could include the
manipulation of polyamine biosynthesis and the topical
administration of selected polyamines, such as spermidine.
Key words: eflornithine – hair – ornithine decarboxylase –
polyamines – spermidine
Please cite this paper as: Polyamines and hair: a couple in search of perfection. Experimental Dermatology 2010; 19: 784–790.
Introduction
A putative connection between polyamines and hair growth
was first established in 1975. Probst and Krebs reported
that the activity of ornithine decarboxylase (ODC), the
rate-limiting enzyme in the polyamines biosynthesis path-
way, changed cyclically in murine hair follicles (HFs), par-
alleling hair growth (1). Subsequent studies replicated these
findings (2,3), providing further evidence for the impor-
tance of ODC, and hence of polyamines, in hair growth.
Consequently, eflornithine, or difluoromethylornithine
(DFMO), a compound that inhibits ODC, has found clini-
cal application in the amelioration of excessive facial hair
growth in women (4). However, the exact function of poly-
amines in the human HF and their mechanisms of action
remain largely unknown, with experimental evidence often
providing seemingly conflicting results.
In this viewpoint, we summarize the current evidence on
the role of polyamines in HF biology, propose hypothetical
mechanisms of action and define major open research fron-
tiers. We close by arguing that a renewed interest in the
‘polyamine–hair connection’ is not only of major interest
for the management of hair growth disorders, but that
exploiting the human HF as a research model also promises
major new insights into the role of polyamines in rapidly
regenerating human tissues in situ, of key potential impor-
tance in our understanding of tumor biology.
What are polyamines?
Polyamines are polycationic aliphatic amines, including
putrescine, spermidine and spermine. These are synthesized
from l-arginine or l-methionine (Fig. S1). Polyamines are
ubiquitous in prokaryotic and eukaryotic cells, where they
are indispensable for cell survival and the regulation of a
DOI:10.1111/j.1600-0625.2010.01111.x
www.blackwellpublishing.com/EXD Viewpoint
784 ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790
bewildering array of biological processes (5–7) ranging
from the control of cell and tissue growth via differentia-
tion (8) to the promotion of tumor growth (9,10). Selected
functions of polyamines are detailed in Table S1.
Coinciding with their essential role in proliferation, they
are synthesized in the G1 phase of the cell cycle, and their
level is increased when transformation or proliferation are
induced by growth factors, carcinogens, viruses or onco-
genes (11–13). The exact mechanisms of their action are
still, for the most part, unknown, and while some of these
effects are specific for polyamines, others may be less spe-
cific and may be attributable to the general cationic nature
of these compounds (14). Polyamines are obtained endoge-
nously via biosynthesis, including synthesis by resident gut
bacteria, and exogenously from the diet (15). Typically,
they are present in fruits and vegetables, foods of animal
origin and fermented food products (16).
As expected from their vital role in cellular function,
polyamine biosynthesis and degradation are tightly regu-
lated by complex molecular pathways, including a number
of rate-limiting enzymes (Fig. S1). The pivotal enzyme in
polyamine biosynthesis is ODC, which is highly regulated,
and is related to polyamine levels during the cell cycle. For
example, ODC peaks in G1 immediately prior to the start
of DNA synthesis and in G2 M (17). Spermidine spermine
N1-acetyltransferase (SSAT) is the key enzyme in the poly-
amine catabolic pathway, which regulates intracellular poly-
amine levels to prevent their over-accumulation which
itself may be cytotoxic (7). SSAT is also tightly regulated;
elevated levels of polyamines strongly induce its expression
and stabilize the mRNA and protein product, while in their
absence SSAT undergoes rapid turnover (7). Spermine can
also be oxidized directly to spermidine by the action of
spermine oxidase (SMO) without the prior acetylation step
(7).
Polyamine biosynthesis by ODC is controlled by cellular
polyamine concentration. This control is mediated by ODC
inhibitory proteins called antizymes, which bind to ODC
and direct it to ubiquitin independent proteasomal degra-
dation (18). Recent studies indicate that antizymes are
involved in degradation of other growth-regulating proteins
in addition to ODC. These include downstream effectors of
bone morphogenic proteins Smad1 (19) and Snip1 (20),
the cell cycle regulatory protein cyclin D1 (21) and the
oncogene Aurora-A (22). Thus, it is likely that polyamines
also interact on growth and organ development by means
that are not attributable to their biochemical structure.
ODC expression and the hair cycle
The HF is one of the most proliferative organs in the body,
with an exceptionally high cell turnover (23,24). It is char-
acterized by an enduring cyclic regression and regeneration,
called the hair cycle (23,25–27). After completion of their
morphogenesis, HFs enter the catagen phase (organ regres-
sion determined by controlled apoptosis), followed by a
relative resting phase (telogen). After telogen, HFs enter the
active growth and hair fibre production phase (anagen)
(Fig. S2).
Given the significance of polyamines in proliferation, it
was postulated that the expression of the key enzyme in
their production, ODC, would correlate with the proliferat-
ing stages of the HF. Indeed, variations in the rate of DNA
synthesis, in murine skin extracts, through the whole hair
cycle correlated with changes in the activity of ODC (1).
ODC activity was virtually absent in skin containing telo-
gen HFs, suggesting that its activity is related to the HFs
and not other cutaneous compartments (28). In agreement
with this finding, Sundberg et al., while evaluating ODC
expression pattern in skin carcinogenesis, have also demon-
strated that in normal murine skin ODC expression was
dependent on hair cycle (29). In telogen HFs, ODC expres-
sion was confined to an area corresponding to the HF
bulge region (the putative site of HF stem cells), and in
anagen follicles ODC expression was evident along almost
the entire length of the follicle.
To better delineate the temporal and spatial expression
of ODC, Nancarrow et al. (30) performed a series of in situ
hybridization experiments in mice which provided evidence
that ODC was expressed in discrete epidermal thickenings
of the embryonic ectoderm, marking the initial phase of
HF formation (30). ODC expression followed the leading
edge of the follicle placode and was present in the cells at
the base of the growing follicle, neighbouring the future
dermal papilla cells. During mouse HF cycle, ODC expres-
sion was cycle dependent (Fig. S2). Comparable results
were also observed in wool follicles (31). It should be noted
that ODC mRNA expression pattern does not always corre-
late with protein expression pattern (Fig. S2). This might
be explained, in part, by the known strong translational
regulation of ODC (32).
The first evidence of human hair cycle stage-dependent
variation in expression of ODC came from the study by Pi
et al. (33), who confirmed that ODC was expressed in the
human HF, both at the gene and at the protein levels.
ODC immunoreactivity was detected in the HF epithelium
during anagen, which was downregulated during the trans-
formation to catagen. Suppression of the keratinocyte pro-
liferation was achieved by gene transfection of HFs with
ODC siRNA.
In summary, the expression of ODC in the HF is vari-
able and closely related to cell proliferation and commit-
ment during follicle initiation and hair growth (30).
Interestingly, the promoter region of the ODC gene
includes several regulatory elements, which have been
shown to be strongly linked to hair growth and cycle (34).
These include, for example, activator protein-1 and -2,
Polyamines and hair
ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790 785
which have been demonstrated to take active part in the
development and homeostasis of epidermis and hair
(35,36). It might be postulated that, at least in part, these
regulatory elements exert their effect on hair growth and
cycle by affecting the amount of polyamines by regulating
ODC expression.
The ‘polyamine–hair connection’: lessons from
transgenic mice
To more clearly elucidate the physiological role of the poly-
amines, several transgenic mouse lines have been devel-
oped, with genetically modified polyamine metabolism
(37). Astonishingly, the most prominent phenotype of these
mice was hair loss. The hair phenotypes of the different
mouse lines, in relation to cutaneous polyamine levels, are
summarized in Table S2.
Surprisingly, the mouse lines overexpressing SSAT, with
the activation of polyamine catabolism, and those overex-
pressing ODC, activating polyamine biosynthesis, both
demonstrated replacement of HFs by dermal cysts, which
corresponded to hair loss phenotype (37). It was suggested
that the common mechanism explaining these seemingly
contradictory findings was the overaccumulation of putres-
cine. This assumption was strongly supported by transgenic
mice overexpressing both SSAT and ODC, which had per-
manent hair loss evident already at the age of 8–9 weeks
(38). The authors proposed that the overaccumulation of
putrescine in the skin shifted the process of HF differentia-
tion towards proliferation, leading to the formation of der-
mal cysts by the proliferating, basal outer root sheath
(ORS) keratinocytes (38,39). This was demonstrated in or-
ganotypic cultures prepared from SSAT overexpressing
cells, which showed similar changes in differentiation (14).
It appears that intracellular putrescine levels behave like a
‘molecular switch’ (39), controlling the behaviour of ORS
keratinocytes. High levels of putrescine retain the basal cell
phenotype of keratinocytes, thus inhibiting differentiation
while promoting proliferation, and low levels accommodate
differentiation but suppress proliferation (14). Additionally,
significantly high levels of putrescine may hinder any fluc-
tuations in putrescine levels because of external stimuli,
thus eliminating exogenous control of HF growth and dif-
ferentiation (39). Strengthening the potential role of
putrescine in changing hair phenotype is the fact that
transgenic mice overexpressing K5 and K6 promoter driven
antizyme, although causing a decrease in polyamine
amount, did not show changes in hair phenotype (40,41).
Gy mice lacking spermine synthase, which did not have
increased putrescine levels, also did not show any discern-
ible hair phenotype (42).
Furthermore, indirect effects, resulting from oxidative
stress exerted by polyamine catabolism products, could also
partly explain the hair loss phenotype in the SSAT
transgenic mice (43). The production of hydrogen peroxide,
by the degradation of acetylated polyamines by polyamine
oxidase, could result in apoptosis (38,44). However,
enhanced apoptosis was not seen in the skin of SSAT over-
expressing mice, and fibroblasts obtained from this mouse
line did not show any change in the anti-proliferative effects
of SSAT induction in response to inhibition of the poly-
amine oxidase (43), providing little supportive evidence for
this theory.
Pharmacological in vitro and in vivo studies
Several studies, both in vivo and in vitro, have provided
further evidence of the importance of polyamines in HF
function. In a long-term anti-carcinogenesis experiment,
mice receiving 1% DFMO in their drinking water were
noted to have severe retardation of hair growth (45).
Another long-term study in which dogs and rats were
administered oral DFMO daily for 1 year showed the ani-
mals had moderate to severe dermatological reactions,
including alopecia and dermatitis, although the alopecia
was attributed to malnutrition (46). In another study,
treatment of protein kinase C transgenic mice with DFMO
led to marked hair loss, accompanied by a decrease in the
number of intact HFs (47).
In the seminal study by Hynd et al. (45),the first to sys-
tematically explore the role of polyamines in hair fibre
growth in sheep, the authors utilized specific enzyme inhib-
itors and substrate deletions to demonstrate the major
effects of ODC and spermidine on hair growth, composi-
tion and keratin gene activity. Systemic administration of
DFMO to sheep led to a decline in the rate of hair fibre
elongation and an increase in fibre diameter, accompanied
by an increase in the amount of fibre occupied by paracor-
tical cells and an increase in the mRNA levels encoding a
cysteine-rich family of keratin proteins. While the adminis-
tration of DFMO to wool follicles in culture did not
change their growth, the addition of methylglyoxal bis-
guanylhydrazone, an inhibitor of S-adenosylmethionine
decarboxylase, completely inhibited hair growth. This inhi-
bition was overcome by the co-administration of spermi-
dine to the media. The addition of spermine or a spermine
synthase inhibitor did not change fibre growth. The fact
that the addition of spermidine could partially overcome
the growth inhibition exerted by deletion of methionine
from the media proved that methionine is essential for the
HF, in part to facilitate spermidine production.
The hair growth promoting effects of spermidine were
also demonstrated by local intradermal injection to Merino
lambs (48), which led to increased mitotic activity in the
wool bulb, accompanied by an increased fibre length growth
rate. No change, however, was noted in wool diameter.
Further support for the hair promoting effect was provided
by a recent study, which showed that topical application of
Ramot et al.
786 ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790
a-methylspermidine, a metabolically stable polyamine ana-
logue, led to induction of hair growth in telogen phase mice
(49). This was accompanied by proliferation of follicular
keratinocytes and upregulation of b-catenin.
In a study evaluating the effects of DFMO on organ cul-
ture of human HFs, Kloepper et al. (50) provided the first
evidence that DFMO promotes anagen–catagen induction,
thus underlining the importance of ODC and ODC-depen-
dent polyamine synthesis for anagen maintenance and for
human HF cycling. In addition, in contrast to the in vitro
experiments with sheep follicles, this study demonstrated
significant downregulation of hair shaft elongation by
DFMO, which was accompanied by a decrease in the
number of proliferating matrix keratinocytes (Fig. S3).
Interestingly, HF melanin content was also reduced in this
study, an important pigmentary effect of DFMO which was
previously unrecognized.
It should also be noted that changes in the levels of
l-arginine and l-ornithine, two key amino acid substrates
for polyamine synthesis (Fig. S1), have been connected to
hair phenotypes. In vitro experiments with cultured human
HFs have shown that administration of arginine or orni-
thine led to improved HF growth rate (51). In addition, a
transgenic mouse model, which overexpresses arginase I in
the small intestine, showed severe distortion of HFs, a
phenotype consistent with delayed maturation of hair (52).
Because excess activation of arginase leads to accumulation
of ornithine, it was speculated that excess production of
polyamines could underlie the distorted hair phenotype.
However, polyamine levels were found to be normal, failing
to substantiate this theory.
Role of polyamines in HF-derived tumorigenesis
There is strong evidence that changes in polyamine metab-
olism are related to tumor growth (9,10,53). This tendency
has also been demonstrated in the skin, where increased
expression of ODC led to increased frequency of skin
tumors, especially HF-derived tumors (54). These included
keratoacanthoma-like and well-differentiated papillomatous
lesions, which corresponded with extremely high ODC-
activity in the tumors (54). Treatment with DFMO, overex-
pression of antizyme, or repression of ODC expression,
blocked the appearance of papillomata, and even led to
tumor regression, further strengthening the role of polyam-
ines in tumor development (40,41,55,56). Indeed, it was
also shown that ODC induction is a necessary step in skin
carcinogenesis, and constitutes a key component in the
Raf MEK ERK pathway (57).
Strikingly, K6 SSAT transgenic mice were also found to
be susceptible to chemically induced skin carcinogenesis,
thus indicating a major role for putrescine or N1-acetylspe-
rmidine in tumorogensis (58,59). Moreover, putrescine
is the most abundant polyamine in papillomata, and
co-administration of putrescine and DFMO blocked the
growth inhibitory effect of DFMO (55). It was suggested
that the increased production of reactive oxygen species
and toxic aldehydes, induced by the elevated SSAT PAO
pathway, led to advanced tumor phenotypes (59,60). It
should be noted, however, that one study showed that
SSAT transgenic mice were more resistant to the develop-
ment of papillomata (38).
In humans, a recent randomized, double-blinded clinical
trail evaluated the effect of oral DFMO in preventing the
development of skin cancer (61). Although there was no
difference in the numbers of new squamous cell cancers,
the administration of DFMO had a protective effect on the
development of new basal cell cancer, which gives hope
that this treatment might be an effective modality in pre-
venting this type of skin cancer.
Clinical evidence in support of the ‘polyamine–
hair connection’
Hirsutism
DMFO was first produced as an anti-cancer drug in the late
1970s (62,63), and later was used intravenously as a treat-
ment for Trypanosoma brucei, the parasitic protist that
causes African sleeping sickness (64). Interestingly, this
treatment led to hair shaft abnormalities and affected the
normal pattern of hair growth (64). Following these obser-
vations, a topical application of eflornithine was developed
as a treatment for unwanted facial hair growth, and eflorni-
thine hydrochloride 13.9% cream (Vaniqa
; Bristol Myers-
Squibb Gillette Co., San Diego, CA, USA) was approved for
this indication in women by the Food and Drug Administra-
tion in August 2000 in the USA and many other countries
(4). Several clinical studies in humans have demonstrated
the efficacy of eflornithine in slowing hair growth with little
adverse effects. Selected clinical trials are summarized in
Table S3. Taken together, these results strengthen the notion
that polyamine synthesis promotes human HF growth, simi-
lar to the effects observed in animals and in in vitro studies.
Keratosis follicularis spinulosa decalvans
The association between polyamines and skin phenotype is
strongly demonstrated by the rare disease keratosis follicu-
laris spinulosa decalvans, which is characterized by follicu-
lar hyperkeratosis (65). One patient was found to have a
duplication of the genome region containing the gene
which encodes SSAT. Accordingly, cultured fibroblasts
from this patient had an increase in SSAT, a reduction in
spermidine and an increase in putrescine.
Do polyamines have effect on HF pigmentation?
Kloepper et al. (50) reported that DFMO led to decreased
melanin content of HFs. However, none of the clinical trials
Polyamines and hair
ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790 787
performed with topical eflornithine described any effect on
HF pigmentation. Nevertheless, previous studies have
shown increased concentrations of polyamines in pigmented
HFs when compared to depigmented HFs from albino mice
(66). This was attributed to the polyanion character of the
melanin polymer, which facilitates its binding with the cat-
ionic polyamines. It is not known whether this binding has
any functional significance, but it presumably serves to sta-
bilize melanin polymers. In contrast to these findings, one
group has reported that the inhibition of polyamine synthe-
sis led to stimulation of melanotic expression by cultured
melanoma cells (67). However, it was not clear whether
these effects were indeed mediated by polyamine depriva-
tion of the cells (68). Recent, preliminary evidence from our
laboratory suggests that the polyamine, spermidine, stimu-
lates melanin production in organ-cultured human anagen
HFs (Ramot & Paus, unpublished observation).
Hypothetical role of polyamines in hair follicle
cycling and growth
The available reports on the effects of polyamines, ODC
and ODC inhibitors on the HF are partially confusing and
can appear contradictory. However, taking into consider-
ation all the observations reported above, the following
hypothesis synthesizes the available data. The expression of
ODC is induced by local mediators in the HF, thus trigger-
ing the anagen phase (39). The growth of the HF and the
anagen phase are maintained by a constant low activity of
the ODC enzyme, producing stable levels of polyamines.
When the levels of the local mediators decline, ODC
expression is reduced, which in turn diminishes the
amount of polyamines, thus initiating the catagen phase.
The inhibition of ODC reduces HF elongation and may
lead to catagen induction, while replenishing the hair with
polyamines may help maintain anagen and HF growth
(Fig. S4). When this tight regulation is disturbed, for exam-
ple by flooding the hair with putrescine, the epithelial
keratinocytes are wedged into a constant state of prolifera-
tion, which promotes the formation of dermal cysts.
The beneficial effect of spermidine on hair growth could
be related directly to its proliferation-enhancing effects on
bulb matrix keratinocytes, which give rise to the various
cell lines of the hair shaft and determine hair length (24).
Additionally, increased exogenous spermidine may decrease
the need for de novo production of spermidine, thus
increasing the amount of methionine and cysteine (48)
available for hair keratin synthesis, which may be stimu-
lated (Fig. S4).
Oxidative stress likely plays an important role in the
induction of apoptosis of hair matrix keratinocytes, thus
leading to a decrease in hair shaft formation and catagen
induction (69). Because polyamines have proven anti-
oxidant properties, including in the skin (70), it is
conceivable that the maintenance of anagen by polyamines
is mediated, at least in part, by protection of the hair
matrix keratinocytes from apoptosis by eliminating oxida-
tive stress. Given the multiple other functions described
for polyamines (Table S1), their hair growth-promoting
effects, as well as the hair growth inhibitory activities of
ODC inhibitors in the human system, the key challenge
in exploring the ‘polyamine–hair connection,’ is to sys-
tematically elucidate to which extent these hair growth
modulatory activities reflect a direct effect of polyamines
as growth factors, modulators of cell proliferation, migra-
tion and differentiation, nutrients and metabolic regula-
tors, DNA RNA stabilizers and modulators of DNA
replication transcription and or stabilizers of membrane
and cytoskeletal proteins (8–10,71,72).
Conclusions and perspectives
There is abundant evidence documenting the importance
of polyamines to the HF, and it is clear that tight regula-
tion of their production is essential for proper hair func-
tion. While polyamines seem to be essential for proper
growth, their abundance may lead to distortion of the HF.
The clinical observation that inhibition of polyamine syn-
thesis leads to decreased hair growth further strengthens
the importance of polyamines. However, their exact mecha-
nisms of action and functions in both skin biology and
pathology require systematic reanalysis.
A renaissance of polyamine research in hair biology, well
beyond the inhibition of ODC activity as hirsutism therapy,
is both promising and important for the development of
novel therapeutic strategies for the manipulation of human
hair growth by targeted manipulation of polyamine biosyn-
thesis and by the administration of selected polyamines
such as spermidine. In addition, renewed interest in the
‘polyamine–hair connection’ is not only of major interest
for the management of hair growth disorders, but exploit-
ing the human HF as an accessible and instructive, clini-
cally relevant research model also promises major new
insights into the role of polyamines in other rapidly regen-
erating human tissues and tumors in situ.
Acknowledgements
The authors gratefully acknowledge the help of Dr. Ewan Langan with text
editing as well as the design of Fig. S4 by Dr. Stephan Tiede. We thank
Dr. Koji Sugawara for providing Fig. S3 [from Kloepper et al. 2009 (50)].
Writing of this article was supported in part by a grant from Manchester
NIHRS Biomedical Research Center to RP.
Conflict of interest declaration
GG serves as vice president for research and development of a company
that markets a polyamine-containing nutraceutical. FR serves as consultant
for this company, while RP holds a research grant from it.
Ramot et al.
788 ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790
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Supporting Information
Additional Supporting Information may be found in the online version of
this article:
Figure S1. Polyamine metabolic pathways, with potential inhibition
points. Ornithine decarboxylase (ODC) is responsible for the de novo pro-
duction of putrescine. It catalyzes the first and rate-limiting step in this
pathway by transforming L-ornithine into putrescine, which in turn can be
converted to spermidine and spermine. Spermidine/spermine N1-acetyl-
transferase (SSAT) is the key enzyme in the polyamine catabolic pathway,
by catalysing the N-acetylation of spermine and spermidine, which can be
then either excreted from the cell or ultimately back-converted to putres-
cine by polyamine oxidase. Spermine can also be oxidized directly to
spermidine by the action of spermine oxidase (SMO) without a prior
acetylation step. In red: rate-controlling enzymes. In green: catalyzing
enzymes. In blue: inhibitory compounds. AdoMet, S-adenosylmethionine;
AdoMetDC, S-adenosylmethionine decarboxylase; BDAP, N-(n-butyl)-1,3-
diaminopropane; DFMO, difluoromethylornithine; MAT, methionine ade-
nosyltransferase; MGBG, methylglyoxal bis-guanylhydrazone; ODC,
ornithine decarboxylase; PAO, polyamine oxidase; SMO, spermine oxidase;
SSAT, spermidine/spermine N1-acetyltransferase. Modified after Gilmour,
2007 (73).
Figure S2. Protein and gene expression in the mouse hair follicle. In
anagen pelage hairs, ODC is profusely expressed in the lower proliferating
part of the follicular bulb. ODC expression is found neither in catagen nor
in telogen. When the telogen HF enters anagen again, ODC is expressed in
the new follicular downgrowth in proximity to the club of the previous
hair, limited to the cells at the leading edge of the follicle plug, thus recapi-
tulating the embryonic development pattern. In vibrissae, ODC expression
is more complex. Like pelage HFs, it is found in the hair bulb, but, in
addition, it is profusely expressed in hair shaft keratinocytes which are not
continuous with the follicular bulb. In addition, expression is seen as a
crescent pattern in the upper follicles in the outermost, basal ORS cells, in
proximity to the follicle bulge. Red: protein immunoreactivity. Green: gene
expression according to in situ hybridization. Based on Nancarrow et al.,
1999 (30) and Sundberg et al., 1994 (29). APM, arrector pilli muscle; B/FT,
bulge/follicular trochanter; CTS, connective tissue sheath; D-SC, dermal-
subcutaneous junction; DP, dermal papilla; E, epidermis; HS, hair shaft;
IRS, inner root sheath; KS, keratinocytes strand; ORS, outer root sheath;
SG, sebaceous gland.
Figure S3. The effects of difluoromethylornithine (DFMO) on human
scalp hair follicles in culture. DFMO leads to inhibition of hair shaft elon-
gation (a), accompanied by increased catagen induction (b). In addition,
fewer DAPI positive cells are found below the Auber’s line (c), less Ki-67+
cells are found in matrix keratinocytes cells (d), and more dermal papilla
stalk fibroblasts emigrate out of the dermal papilla following DFMO treat-
ment. DFMO also leads to decreased melanin content in the dermal papilla
(f). *P< 0.05, **P< 0.005. Reprinted with permission from Kloepper et al.
2010 (50).
Figure S4. Connection between polyamines level and the hair follicle
cycle. In addition, several suggested mechanisms by which polyamines lead
to hair growth are summarized.
Table S1. Selected functions of polyamines.
Table S2. Transgenic mice strains with genetically modified polyamine
metabolism and their hair pheotypes.
Table S3. Selected clinical trials with eflornithine cream.
Please note: Wiley-Blackwell are not responsible for the content or func-
tionality of any supporting materials supplied by the authors. Any queries
(other than missing material) should be directed to the corresponding
author for the article.
Ramot et al.
790 ª2010 John Wiley & Sons A/S, Experimental Dermatology,19, 784–790
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Polyamines (putrescine, spermidine and spermine) are required for optimal growth in all cells, and are essential for cell proliferation and growth of cultured wool follicles, with an optimal concentration of spermidine required for the fibre elongation. The effects of a local supply of exogenous spermidine on the rate of cell division in the wool follicles, the length growth rate and diameter of fibres were therefore examined in Merino lambs. Three groups of eight lambs (40kg) were given food at 1.2 × maintenance. Spermidine was injected intradermally into a small patch (3 × 3cm) on the left flank three times per day for 7 days at one of three concentrations: 1.38, 2.75 or 4.58 μmol in 0.8ml volume. The same volume of saline was injected into the contralateral side as a control. The concentration of spermidine in the skin patch 3 h after injection on day 7 increased by proportionately 0.18, 0.33 or 0.41 (P < 0.001) respectively. The rates of cell division in the follicle bulb 3 h after the spermidine injection were proportionately 0.104, 0.184 and 0.283 higher compared with the contralateral side (P = 0.078 overall) for the low, medium and high doses of spermidine respectively and differed between the three doses (P < 0.05). The fibre length growth rate, as measured using autoradiography, was proportionately 0.099, 0.117 and 0.156 higher than that of the contralateral side (P < 0.001 overall) for the low, medium and high doses of spermidine respectively, but differences between doses were not significant (P > 0.05). Spermidine injection did not result in a significant change in fibre diameter during the treatment period. The ratio of fibre length growth rate to fibre diameter was increased by the injection of spermidine (P < 0.001). The results suggest that injecting extra spermidine into the skin altered spermidine homeostasis in the skin, stimulated cell proliferation and resulted in increased fibre growth.
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We recently generated a transgenic mouse line with activated polyamine catabolism due to overexpression of spermidine/spermine N1-acetyltransferase. Phenotypic changes in these animals included permanent loss of hair at the age of 3 wk. We have now further explored development of hair loss during early postnatal life. The first hair cycle appeared to be completed normally in the transgenic animals. At postnatal day 15, although macroscopically indistinguishable from their syngenic littermates, the transgenic animals already showed microscopically signs of hair follicle degeneration. Wild-type mice started their second anagen phase at day 27, whereas the transgenic animals did not display functional hair follicles at that time. Hair follicles were replaced by dermal cysts and epidermal utriculi. Analysis of skin polyamines revealed that the transgenic animals continuously overaccumulated putrescine. The view that an overaccumulation of putrescine was related to the disturbed hair follicle development was strengthened by the finding that doubly transgenic mice overexpressing, both spermidine/spermine N1-acetyltransferase and ornithine decarboxylase and with extremely high levels of putrescine in the skin, showed distinctly more severe skin changes compared with the singly transgenic animals. Interest ingly, in spite of their hairless phenotype, the spermidine/spermine N1-acetyltransferase transgenic mice, were significantly more resistant to the development of papillomas in response to the two-stage skin carcinogenesis. Analysis of skin polyamines indicated that the syngenic mice tripled their spermidine content when exposed to promotion, whereas the transgenic animals showed only modest changes. These results suggest that putrescine plays a pivotal part in normal hair follicle development.