Growth factors and cytokines in

insights from
and the potentials

Hair growth disorders, particularly those that lead

to halr loss (alopecia), are common and frequently
cause significant mental anguish In affecter;
individuals, The mechanisms underiylng the
ma)ority of these disorders are unknown. However,
insights into the specific molecular mechanisms of
hair foiiicie development and cycling have recently
been made using animal models, partlcuiariy mice
that over* or underexpress a specific gene for a
growth factor or cytokine. Other animal madeis
have demonstrated that certain growth factors and
eytokiner can prevent much of the alopecia caused
by cancer chemotherapeutic agents. These animal
models have confirmed the importance of growth
factors and cytokines in hair follicle development
and cycling, and have formed the foundation for
potential clinical therapy of hair growth disorders,
particularly alopecia. Nevertheless, important
questions concerning their efficacy, safety and
delivery will need to be answered before
successful clinical therapy of any hair growth
disorder becomes a reality.

HAiR growth cycles through three phases:anagen or the active

growthphase.catagenor the intermediatephase.and telogenor the
resting/inactivephase. This cyclical growth of hair had long been
suspected to be regulated by soluble factors, but their identities

Copyright819% ElsevierScience Ltd. All rightsramed. 1357 - ~310/96/!515.00 P11:Sl357-43lo(%NO4S-9

 Table1. Somegrowthfactorsandtheirreceptors
thathavebeenlocalizedto hairfollic!es
Qrowutfactor Follicular Raceptor(s)and Knownefleetts) on or function(s) spsciesfKHnwftichdsta
distribution distribution in hair foltfcte a4-edsrivsd

Epidennalgrowthfactor root-sheath
Outer EGF receptor:outer root- Delays follkulardevelopment; induces HUrlltUl(i~vitn,and
(EGF) sheath, bulb matrix follicle regression and retards hair growth tissue); mows; sttee@O
and cycting

Transforminggrowth Outer rool-sheath, EGF receptor: outer rool- Necessary for normal follicular positional Mwse~2
factora (T0F-a) inner root-sheath sheath, bulb matrix development; retards hair growth

NW differentiation
factor Uncertain:mightnot HER-O: outer root-sheath Unknown Human (twue)
(NDF)/heregulin be foundin follicle HER-S outer root-sheath,
inner root-sheath

AddkfibroblastgmwIh Outer root-sheath FGF receptor 1 (FGFRl): Delays follicular development; retards hair Mouse? shsep14
factor (aFGF) dermal papilla; FGF growth and cycling
receptor 2 (FGFR2): outer
root-sheath, bulb matrix;
KGF receptor (KGFR):
outer root-sheath, bulb
matrix

Basicfibroblastgrowth Outer root-sheath FGFRl : dermal papilla Delays follicular development; Mouse? sheep
factor(bFGF) FGFRB: outer root-sheath, retards hair growth and cycling
bulb matrix

Rbroblastgrowthfactor 5 Outer root-sheath Specific receptor uncertain, tnduces transitton from anagsn phase
(FGW possibly FGFRl-FGFR2 01 hair cycle to catagen phase
ditner

Keratlnocyte growth factor Dermal papi% KGFR: ouler root-sheath, Stimulates folticular prollleratlon: MOUSda

(KQPI bulbrnatrfx Induces normal dlfferentlatlon and
keratinizationof hair
Transforminggrowth lrmr root-sheath, Several receptorswithwide lnhibltsfollkulardevelopment; Human(in vIfro)?mouse
factor(3(TGF+J) outer root-sheath, follkulardistribution inhibitsfollkular proliferation
superfamily bulb matrix,dermal
papilla
Hepatocytegtwthfactor oermalpapilla HGF receptor:foflicular Stimulatesfollicularprotiferalron Human (in vifm)g; mousafe
(HGF) epithelium,specificlocation
UrWp3Cified

growthDermalpapilla
vascularendouldial VEGF receptor: dermal Stimulatesdermalpapilla(uncertain) Human (ti8sue)2
I *rap
factor(VEGF) papflla (uncertain)

Parathyroldhormone- Hair follicle,prsciss PTHrP receptorz ktcation in Inhibitsearfy fofliculardevelopment; Mousea2

retatedpmteln(PTHrP) tocationuncertain fofiicle undetermined antagoniststimulateshair growth
Insulbt4ikegrowthfactor 1 Dermal papilla IOF- receptor: foflicular Prevents entry of follicle into catagen Human (in v&o)
(IGF-1) (u-) location uncertain pha=

lnterfeukln1 (IL-l) Anagen follkfe, IL-1 receptortype I: Inhibitsfollkular proliferation

speolfk locatkn follkularepithelium,
UnCettM probablyouter root-sheath

461
 M<3LkXXJLAW ML3DlCINE IXX~AY. NOVIiMNliH I996

growth factors and cytokines that have

b Catagen c lelogen been provedto intluencehair follicle de-
a Anagen
velopmentor cycling k ho rather than
in organcultures,and will thenfocusfur-
ther on those few growth factors or
cytokinesthat have shown the potential
for human therapeuticbenefit by stimu-
lating hair growth or preventinghair loss
in animal modelsof alopecia.

Newinsightsinto the follicular

functionsof growthfactorsfrum
animalmodels
Administration of growthfactors
a$ects hair growth in normal animals
o Outer root-sheath Since most growth factors and cyto-
I Inner root-sheath kines have never been administeredto
TOF-ps, KGF; EGF, TGF-a, TGF_Ps, I Bulb matrix humans. and the few that have been
HGF, VEGF, bFGF, FGFS, EGFR, I Dermal papilla administeredhavehad no apparenteffects
FGFRl KGFR, HER-IL, HER-3 CJ Bulge on hair, animal modelshaveprovidedus
with nearlyall of the informationwe cur-
Agure 1. the humanscalp-hairgrowthcycle showingthe localizationof some importantgrowthfactorsand rently have on the follicular effects and
their receptorsin the follicle(see also Table 1). The follicleprogressesfrom (a) the anagen (growth)phase
to (b)the catagen(intermediate)phase with upwardmigrationand shorteningof the follicle[arrowsin (b)] functions of growth factors and cyto-
leadingto separationof the bulbmatrixand dermalpapilla,The folliclefinallyenters (c) the tafogen(resting) kines. In addition, animal models will
phase whenthe hairfollicleand shaft have maxlmailyshortened.The bulgeregionis believedto containthe continue to be useful in the future to
hair folliclestem ceils, and it has been hypothesizedthat activationof the bulge regionduringthe telogen determine the therapeutic potential of
phaseis criticalto maintenanceof the hair growthcycle by inducingthe transitionfromtelogento anagsn, variousgrowth factors and cytokines in
As kera)i#tcytegrowthfactor (KQF) and hepatocytegrowthfactor (HGF) are both producedin the dennai
papllle , they mightplay an importantrole in bulgeactivationdur;q telogen(arrownom dermai papiiia to thetreatmentor pnzvention of alopeciaThe
bulge).Vascularendotholialgrowthfactor(VEQF), whichis also producedin the dermalpapilla*, mightalso first strongevidence that growth factors
play a role in autoorlnestlmulatlonof the dermal papillain telogen dv,mg bulge activation(circulararrow). andcytokinesplayedan importantrole in
Abbrevlatlons:aFGF, a&fio flbroblastgrowthfactor;bF4F, basic fibroblaetgrowthfactor:EGF, epidermal rcgulutinghair developmentml cycling
growthfactor;EQFR, EGF receptor;FC4Ff5, fib&last growthfactor5; FGFRl, FQFR2, FGF receptors1 and 2,
respectively;HEfW WER-3,humanepidermalreceptors2 and 3, respeotively:KOFR, lW raceptor;WE-W, came from observationsmade lbllowine
transforminggrowthfactor ((I:TOF$s, transforminggrowthfactor p superfamilymemoetb. Modified,with systemicadministrationof purified, and
permission,from Ret, 4, later recombinant, growth factors and
1,./..I_,P %/tlaxm: ._.. i. _j:.-._ i_ =%__ . ,, .I
cytckincs in narmul animals. WI= was
one of the lirst purilicd growthfactorsto
now known, from mcent stud& in isolatedhumanand murine hair be udministcr4 systcmicully,and wus Iou~rd to delay hair follicle
follicla organcultureSystsms, tts well tts scverul unimul mod4 sys- development,delay hair cycle initiation and progression.and retard
tems,that numerousgrowthfactors,cytokinesand their receptorsare hair growth.A studyexaminingetlectsinducetiby systemicadmin-
presentin hair follicle& including the bulgeregion! and that these istrationof TGF-o found that this member of the EGF family also
factorsinfluencethe development,growth and cycling of hair folli- delayedhair follicle developmentand retardedhair growth(Ref. I I ).
cles in a variety of way? (Table I and Fig. I). In addition. alter- Exogenousadministrationof either aFGF or bFGF also r~arded
ations in growthfactorsand their receptorshave been implicated in hair follicle developmentandhair growthund cyclin$. In contrastto
severulhumanhair disorders,particularlyalopeciuS, and specifically the inhibitory follicular effects of these two membersof the FGF
alopeciaareuta,an immune-mediateddiseasetargetedat the f~~llicu- family. administrationof KGF stimulatedproliferationof heir folli-
lar butti? cles, and even inducedhair growth in athymic nude (IM/NN) mice.
The list of growth factors and cytokinesknown to have direct whereulopeciuis due to u defkct in follicular keratinization (Fig. 2).
effects on hair follicles is long, and includes members of three To our knowledge.other than the five factorsdiscus& above(EGE
important families of growth factors: the epidermal growth factor TGF-a, aFGE bFGF and KGF), no other growth factorsor cytokines
(EGF) family, such as EGF* and transforminggrowth factor cx havebeenshownto haveanyetrecton hair follicles k rive following
(TGF-0: the tibrt,blast growth factor (FGF) family, including exogenousadministrationin any animal model system.
acidic FGF (aFGF), basicFGF (bFGF). FGFS (Ref. IS) and FGF7 Although no other factorshavebeen shownto atfircthair follicles
or keratinocytegrowth factor (KGF); and membersof the trans- in V~RJ,a short peptide antagonistto PTHrP has stimulated hair
forminggrowthfwtor g (TGF-g) superfamily.such as TGF-IpI (Ref. growth in another mutant mouse model of alopecia. the hairless
18). Other factors, such as hqxttocyte bmwth factor(HGFP. vascu- mot&, in which alopeciais due to a failure of the detmal papilla to
lar endothelial growthfactor(VEGF). parathyroidhormone-related m-join the hair follicle following the first hair cycle. In addition.
protein @THrP)? insulin-like growth factor I (IGF-I , and inter- thereare currentlyat leasttwo othergrowth factors.HGF andVEGF,
leukin I (IL-l )S havealsobee11 foundto affecthdirfollicles in oneor that have not yet been testedirr ritpo,but might eventuallybe shown
more systems.This review wi:l concentrateprimarily on those to havebeneficial effectsin alopecia.HGF has beenshownto be an
-
 The tirst identitication of the specific functions that growth fxtors
have in hair follicle development and cycling have come rehtively
recently with the development of pene deletion (gene knockout) tech-
110i0~y (SW Tilbit! 2 for sulllll~ilry). The iirst growth fxlur dciicieucy
coi-resl~ondingt0 il kllOWll Ililir-UKll lMllillilMl WilL discovered Wll~ll
the gene for TGF-ru was d&red, ilnd the result@ TGF-cu ~IWC~OU~
mice developed ti wuved huir coat and whiskers. ;L phenotype that
was contirmed to be genetically identical to the ~~~~~u~liyoccuknp
waved- I mutation ( wo-I ) (Fig. Al). Shortly itficrwitrds. dsirrtion 01
the EGF reccpior (EGFR) wus found IO re4t in ;UI ;rlln~M idenrkrl

liable 2. hansgenic and knockoutmurine modelsfor determiningthe functionsof growthfactors in hair

growth,developmentand cycling
Murine modef Ph-VP@ ilfdty wflfl naluraffy Fdilcular fmction(s) of growth factor
wcutrlng murfno mufant

Transfonnlnggrowthfactoro (TGF-a) Distortedand Not epplkabl~(NA) TGF-u is apparentlyn nomuMfollkutarouter

trarwgenloto foiliaularouter root+bhea~fl flattened
hair follicles roobhsnth positional

TGF=udaktlon~* Wavy haircoat Waved-l (w-f) Confirmedthat TOE- Is n for normalfotlkuler

outerroot=sfwth poeftkn t
Epldamtaigrowlhfactorreceptor(EGFR) Wavy haircoat Waved-2(wa-2) rlgnallng (though EGE TGF-a or ottwrfectors)is
EGFR
doktion@ nwwwy for rwwf foflkulatouterrwbfihwth poeHbMlr
-kwnt

Karatinwyte growthfactor(KGF) Markedr&crease in hafr NA KGF la upparengy

tranqanktofoitkubouterroot-sftea~ foiikieden8lty halrfoiikiedensfty

IbmfmtntqatM mutationof KGF muqtor Ma&d decrease In hair NA KGFR dfjrwllngk rw~~tu~ryfor dtwkfwnaoll of normai
(KGFfQtransgmktofoHkuiarouterroot- folikiedensfty halrfollkkdwfty
sheath(~KoFRUeietkn)~
KGF d&&n Rough,unkeptfmlr coal Pmbabiyidwkaf to KGF IONKI@IWJfw n~rmaicifffmntlafh and
rwgh (M ker8tlni~ of hair

TGF-@l twgenic to dlfferentiatexi ~t=ivewighlly

ke&koqtes ln epkknb and folikuier strekhed skinWWI
innerrooMheath markeddecrease in hair NA TGF$l is apparentfynaceswy for development
ot
folikiecien8ity normalhairfolikiedendty

Pamthyroidfwmwne-reifw protein Los8of halr alongventrum NA PTHrPi6 appamkntly

necu66afyfor normalhairgrowthIlrti
(Plliff) fmmqedc to fdkular outer dvefopment
rooMhwW
 MOLECULAR MEDICINE TOI~AY. NOVEMt3EW 19&h

exhibitedabnormalitiesin follicular motphology~? Although both follicular differentiation defect or the PTHrP antagonist foi the
studiessuggestedthatKGF is squired for normal hair follicle devel- hairless-mouse demxal-papilladefect)mightnot be of muchtherapeutic
wnt, the sl.#lcific findings in these two transgcnic models benetitfor many formsof alopeciain humans.However,if defectsor
appeared to be contradictory. It is very likely, however. that constant deficienciesin specificgrowthfactorsor cytokines\tpeTp
foundto be the
-ted overproduction of KGF in the KGF-overexpressing underlyingcausesof specific inherited forms of human alopecia. then
transgenic mice could have overridden normal follicular growth con- therapy with the appropriate factor(s) would be of obvious benefit.
trol mechanisms and inhibited follicular development, while the loss Unfortunately, no defect, deficiency or overproduction of a growth
of KGF signaling during hair follicle development in the KGFR factor or cytokine has yet been confirmed as the cause of any form of
dominant-negative mutant transgenic mice had a similar effect on alopecia in humans*. On a positive note, however, loss of VEGF
foUiculardev&pme!nt. Regardless of the specific mechanisms of their from alopecic hair follicles~Y.as well as follicular overproduction of
cf&ts, both transgenic mice demonstrated that KGF was one of the IL-I and tumor necrosis factor OL (Ref. 30). have both been implicated
endogenous growth facrors important in the regulation of early hair in the pathogenesis of alopecia areata in humans, supporting the
follicle development. A very recent study in which the Kgf genewas importance of continued research into the role of growth factors and
deleted in mice has confirmed that KGF is requiredfor normal follicu- cytokines in specific forms of human alopecia.
tar development and the maintenance of a normal hair coat. Kc- Another common form of alopecia in humans is the acquired ulo-
mice were normal in every regardexcept for exhibiting a rough and pecia associated with cancer chemotherapy or radiation therapy*J.
unkept hair coat (Fig. 3b), a phenotype very similar to the naturally This is a common, and often disturbing, adverse side effect in many
occurring mutation. rough 0~). The K&gene and the ro gene have patients receiving chemotherapy. in fact. a recent study indicated that
been mapped to the same vicinity of mouse chromosome 2, but patients receiving chemotherapy rauked hair loss abovevomiting as
identity between the two genes has yet to be firmly established. an importantconcern. In contrast to the relatively pooroutlook for
successful treatment of inherited forms of alopecia by growth factors,
The potentials for clinical therapy the potential for successful pevenrion of acquired forms of alopecia
Alopecia, or hair loss, is the most common hair growth disorder by pre-treatment with a growth factor or cytokine seems much greater,
in humans and is often the cause of great concern in affected individ- because the mechanism of alopecia induction by most chemothera-
uaIs. Most common forms of alopecia in humans are not very well peutic agents is known. and at least four growth factors or cytokines
understood genetically, and are probably due to a number of different have provided some degn?e of protection from alopecia induced by
factors, only some of which are genetics*27.Androgenic alopecia chemotherapy in animal models using at least one agent, cytosine
(male-pattern baldness), for example, is extremely common, yet its arabinoside ( ARA-C)Qz*sJ . lnterleukin 18 (IL-l p) was the first factor
underlying cause is still not well understood, although it does appear shown to prevent much of the alopecia associated with ARA-C chemo-
to have a genetic predisposition, Other forms of alopecia that therapy in a neonatal rat model (Fig. 4p. More recently, the growth
to have a genetic basis include rrlopecia areata as well US factors EGF. aFGF and KGF have also been shown to plu?ventmuch
other less-common forms of genetic alopeciaglaThis . heterogeneity of the ala cia associated with ARA-C chemotherapy in this neonutal
in forms of alopecia with a possible genetic basis in humans suggests rot modeloe *. lJnfortunately, none of these four factors protected the
that the administration of a growth factor or cytokine that can comet neonu~al rats from the alop& inducedby unothcrcommonly used
u single defect in hair growth or cycling (such as KGF for the W&IU chcmatherapcutic agent, cyclsphosphamide~~, ARA-C is II coll-
cycle-specific chemotherapeutic agent; II
selectively damages proliferating cells
that are in S phase (synthesizing DNA).
By contrast, cyclophosphamide is a cell-
cycle-nonspecific chemotherapeutic agent
that alkylates nucleic acids, thereby in-
ducing cell death in all proliferating cells
regardless of their phase in the cell cycle.
It is very likely, therefore, that IL-lg.
EGE aFGF and KGF can p~tect only
follicularkeratinocytesthat SIRin S phase
from chemotherapy-induced damage,and
that this will limit their potential thera-
peutic use to the prevention of alopecia
induced by chemotherapeutic agents.such
asARA-C, 54luorouracilandmethotn.xate,
that selectively damage only cells in S
phase.

As mentioned earlier, it has been

known for some time that hormonesplay
a major role in the development and
cyclingof hair follicles. It is beyondthe
 Alopecia - Clinical condifion characterized by complete or almost
completelossof hair.
Anagen n The actively growing phase of the hair growth cycle.
Approximately85-M% of human scalp hairs are in anagen.
Autocrine sigae!h!g - A hormone or growth factor influencesthe
behavior of the cell by which it is produced.
Bulge - The compartmentof the hair follicle that has been hypoth-
esized to contain the hair follicle stem cells.
Catagen - The transition phase of the hair growth cycle between
anagen (the actiiely growing phase) and telogen (the resting
phase). Approximately l-2% of human scalp hairs are in catage?.
Domlnant~negativemutation - A mutation that renders the
mutated protein functionlessand, when overexpressed as a trans-
gene, also inhibitsthe function of the wild-type protein.
Knockout mice - Mii that have been genetically engineered tc,
have both alleles of a gena of interest deleted in order to analyze
the function(s) of the deleted gene by observing the effects that
complete absenceof the gene has on the mice.
Pamcrlne signaling - A hormone or growth factor influences the
behavior of adjacentcells.
Telogen - The resting phase of the hair growth cycle. Approxi-
mately lO-15% of human scalp hairs are in telogen.
Tiansgenic mice - Mice that have had an exogenous gene of
interest stably introduced into their genome. The introduced gene
is under the control of a promoter that directs overexpression of
the gene, generally to a specific target tissue, thereby greatly
amplifying its effectsin the tissue ot interest in order to better study
Figure3. Knockoutmice lhat have furtheredour understandingof specific
the genes function. growth factor functionscn hair follicle developmenL (a) A WanstormIng
growth factor CYknockout mouse ( -/- ) has wavy fur and wiiiskero corn-
pared with a normal mouse (A), a phenotype previously described in the
naturallyoccurrrngmouse mutant waved-l (reproducsd,with permission,
from Ref. 12). (b) A keratlnocylegrowthfactor knockoutmouse (-I-) has
scope of this miew to cover as extensive UII (LIU QSthe O~npMc a rough coat compared wilh a normal mouse (+/+), a phenotypa very
potentialof hormonesin human hair disorders.However, in summary, similarto a previouslydescribednaturallyoccucvingmouss mutant rough
(reproduced,with permission,from Ref. 17).
informationregardingthe role of hormones in human ulopcciir is well
ahead of that regardingthe role of growth factorsand cytokines in j
human hair disorders,yet the developmentof successfulhormone-
based therapeuticsis still in its infancy. Most of the attention con-
cerning the useof hormones as therapeuticsin humanshas centered
on two areas:female hirsutism(excesshair, for example on the face)
and androgenicalopecia or male-pattern baldness in both sexes. Unfortunately, undesirableside elTeccs associated with the sys-
Hormone-basedtherapy for both disordershas focusedon blocking temic administration of growth factors or cytokines are a major
the effects of androgensvia small molecules that are capable of impedimentlo their USCas therapeuticsfor alopeciaas well. Many ot
antagonizingandrogensor androgen receptorsWhile
. small-molecule the growth factorsand cytokinesdiscussedin this review, when ad-
anti-androgens can be taken orally, which is advantageous,anti- ministered systemically, have been proven to induce toxic or undesir-
androgenictherapyhas been associatedwith other,unwantedsystemic able effects on multiple organ systemsJJ3 making
, a systemicroute
side effectsbecausethe receptorsfor most steroidhormones,inciud- of administrationfor the preventionor treatmentof alopecia, which is
ing ancbogens, are nearly ubiquitously distributed.As most growth not life threatening,unlikely unlessit is as a secondarybenefitto the
factorsand cytokinesare producedand act 1uculf.vat the hair follicle, use of a growth factor or cytokine for a more seriousmedicalcondi-
it is hoped that a better understandingof the specific functions that tion. Nevertheless,while topical applicationwould initially appearto
growth factorsand cytokinesplay in follicular biology might lead to be an attractivemode of delivery,all of thesefactorsare proteinsor
the developmentof a far more specific and localized therapy than fairly large poiypeptides.which cannot readily penetratethe lipid-
would be possiblewith hormonesor anti-hormonaltherapy. rich stratum comeum of intact skin. Therefore, several different
-
465

delivery systemsto enhanceprotein penetrationthroughthe stratum
corneum of intact skin have been used. The two most successful
approachesto date have been (1) encapsulationof the protein within
lipid-bilayercomplexes(liposomes)in ordeeto makethemmore lipid
sol&i@ and (2) deliveryvia formationof air pocketswithinepider-
ti ke&nocytcs by low&equency ultrasound3While . these two
Mivety systemshavebeenthe mostsuccessfulto date,neitherone has
yet provedto deliveradequateamountsof proteinto the hair follicle
to be of therapeuticbenefit.On an optimisticnote, however,a recent
study Wed some degree of protectionagainstdoxorubicin-
inducedalopecia in a neonatalrat model via the topical delivery of
anti-doxorubicinmonoclonalantibodies (antibodiesare large pro-
teinsof approximately150kDa)encapsulatedin liposomes3B. This is
the only report to dateof successful therapy or prevention of alopecia
via topicaldeliveryof a largeprotein in an animalmodel,albeit not a
growth factor or cytokine. To our knowledge,there have been no
1 tion of a sufficientquantityof the gene product (protein)to give the
MOLECULAR MEDlCtNE TODAY. NOVBMUER IVY6
reports of successful therapy or prevention of alopecia via topical
deliveryof any proteinin humans.
Anothermethod of topicaldeliveryof growth factorsor cytokines
under current investigationis delivery of the gene encoding the
growthfactor/cytokineto the hair follicle rather than deliveryof the
protein itself. This method has the theoretical advantagethat thera-
peutic geneticmaterial will becomeincorporatedin residentcells of
the hair follicle with sustainedlocal productionof the growthfactor
or cytokine by the patientsown cells, without the undesirablesys-
temic side effects associated with systemic delivery of a growth
factor-or cytokine-encodinggene.There has been one report of suc-
cessfultransfectionof a reportergene to murinehair folliclesin rive
using liposomal gene transfeti9,and one report of a reduction in
tumorgrowthin a mousemodelvia transdermaltransferof cytokine-
encoding genes using accelerated gold particlesw. However, we
are unaware of any reports of successfulfollicularor even local cu-
taneousdeliveryof any genethat has resultedin the sustainedproduc-
desired,localizedbiologicaleffect in an animalmodel.In addition,to
our knowledgethere have not been any attemptsat gene delivery to
hair follicles in humans.This inabilityto produce sufficientprottin
for a sustainedlocalized biologicaleffect is the major limitationof
the currently availablegene transfertechniques,and will have to be
resolvedbefore gene therapycan become a viable mode of follicular
growthfactor therapy.
Conclusions and future directEons
While the specific functions that many growth factors and cyto-
kinesplay in hairdevelopmentand cycling have been uncoveredover
the pastdecade,there are obviouslyseveralunresolvedquestionsthat
must he answered before growth factors or cytokines can he used for
the treatmentor preventionat any hair growthdisorder.parliculurly
alopecia. First. the underlying molecular basis of most forms of
humanalopeciamust becamebet&rdefined in order IOidentifywhur
types of alopecia, if any, would he logical candidates for therapy with
specific growth factors or cytokines. Second, appropriate animal
models that closely mimic specific forms of human alopecia must he
humanscaused by

identified in order to assess uccurately rhc porenrial ~her-:~~u~icefii-
~lrcy of a pmiculur growth facror or cytokine in it qxcific form of
alopecia. Lastly, the issne of effeclive dclivcry of grwth factors ctr
cytokines without undesirable systemic effects for the prevention or
therapy of iIlopccia, Lvhich is not life threatening. must be resolved
before grow:h factors or qrokirrcs will be considered for use in
humans. In the realm of topical delivery alone, furtherresearch into
and developmentof new formulationsfor the delivery of proteins and
genes will be necessarybefore the safe, effective and sustained deliv-
ery of growthfactorsor cytokines to hairfollicles for the treatmentor
preventionof alopecia becomes a reality.
Achowl~ments. We thankAngela Rossfor the illustrationfor Fig. 1and;Irsistuncu 23 Wysolmerski.J.J. ef al. ( 1994)
with the layotu of all other figures. and Dr Regina M. Housley for critical review of
the nutnuscrip~.
1 Ebling. F.J.G.(ICWO)Hormonal control of hair growth. in If& c~ui ffuir
Distuses @rfmws. C.E. and Happle. R.. eds), pp. 267-299. Springer-Vet&
2 Panareno. B.A. (1993) Geneexpressionof pntentielmorpbogens during hair
follicleand toothformation:a review.Rq&. F&l. Der:5. .1-l_%360
3 Hardy. M.H. I 19021Thesecwt life of the hair follrlc. Trtwa\ C;C~C~.
X.55-6l
4 Cotsarelis.G.. Sun, T-T. and Lavker. R.M. ( IYW)Label+etainingcellsresidein
the bulgeareaof the pilosebaceow unit: implicationsfor follicularstemcells,
balr cycle,and skincarcinogenesis. Ce//6 1. I 3% I 337
5 Sundherg.J.P. and King, LE. (19cJ6) Muusemutationsas animal modelsand
biomedicaltoolsfor dermatological research,J. /nr*esr. Dermrul. 106, M-376
6 Akiyuma, M.. Smith. L.T. and Holbrook, K.A. (1996) Growthfactor and growth
factor receptoriocalizutiouin the hair folliclebulgeand ussociated tissuein
humanfetus..I./~tws~.lknw~~/. 106.39l-396
7 Prigem. S.A. (I nl. I 19921 Expressionof tbe c-rrbR3
proteinin normalhuman
adult and fetal tissnes.
&lrqtnP 7, I173- I27H
H Philpnu,M.P., Smlerc, D., Wrs~gw GE. ad Kc&y. T. (19Y41 Humuu hair
flrowtbIn v&w ~tmodelfor the studyof bair folllclobiology,R Demml. Sci.
7. s55-s72
9 Moore, G,I?M., P~~II~~, I.+.A. WI Roltirts~ I), I I%.I I I:ldderrnulgrowthfuc-
tot debysthedevelopment of the epidermisundthe buir fulliolcstl micedur-
ing ~rowtbof thefirst 4~41t.&4. f&. 2&X49-55
IO du Cros,D.L., Isuscs,K, uudMoore,O.RM. (1992) Lucalixatinnof epkkrntsi
GrowthfactorimmunoreactMty in sheepskin duFingwool Wllcle develop
ment.J. /~tresr.Dwtntm/. 98, 109-I 15
II Turn,,J.l? (1985) Physiulogicaletkts of transforminggrowth factor in Ike
newbornmouse,S&tt~e 229,673-675
12 Lucu&, NC, e/ ul. 0993) TGFa deficiencyresultsin hair follicle and eye
abnormalitiesin targetedand waved-l mice,Cell73.262-278
13 du Cros, D.L. (1993) Fibroblmtgrowthfactor influences the development and
cyclingof murbtebair fblli&s, Dtv. 6ioL 156.444-453
14 du Cros.D.L.. Isuacs.K. und Moon. GEM. 1993) Distributionof acidicand
basicfibroblastgrowthfactorsin ovine skin during follicle morpbogercsis.
J. Gel/ Sci. 105.667-674
15 H&a J.M., Rosenquist,T., C&z, J. and Martin, G.R. (1994) FGFS us a regu=
lntor of the hair growthcycle:evidencefrom targetedand spontaneous mu=
talions,Ceil 78, iOl7-1025
16 Daniienko,D.M. et al. (19951 Keratbtocytegrowth factor is an important
endopous mediatorof bair follkle growth,development and differentiation:
nonnaltxationof the nulnu follicnlnrdHferentiatbndefectnnd amelioration
of chemotherapy4nduced alopecia,Atu..I. Purhd. 147.14-S-154
17 Ciuo.L.. Degenstein, L. and Fuchs.E. (1996) Kerutinwylegrowth factor is
required for hair developmentbut not for woundhealing.Genres Dev. IO.
165475
Reviews
IS
t9 Sh~maokt.S.. Imaa.R .~ndOp~\\a. H. f i3Y41 Dermal papillac&s e\pre=shepr\
toqte grwth fuctcrr.J. Deny& SU.7. SW-SK?
10 hdo T. ~rM ( 19931 Heputtqie growth factor scat(er factor stimulate hair
grow*b of mousevibrissaein organculture.J. hwesr.Dermzml. 103.306309
21Hoffmm. R. ef ul. t 1996)Cptokines and growthfactorsinfluenceba& growth
in rifro - possibleimplications for the pathogenesis and treatmentof alop&a
areata.AtA Denwtol. Res. 288. 153-l 56
XTL;lchgs.S. er ~1. ! 1996)Vascularendotbelialgrowthfactor is an autocrine
growthfactorfor hair dermalpapillacells. J Inwrt &~w~l. 1%. 17-23
Overexpression of parathyroidhormone-related
protein in the skin of transgenicmice interfereswith hair follicle dew&p
ment,Pnr. i&r/. Acctcl. SC?.U. .S.A. 91, I 133-1 I 37
Htdich. M.F. PI ul. ( lN4) A purath>roid burmune ant;lgtii.i$8stimulates qi-
dvrmal proliferation and hair growth in mice, Pw. .1jt/. .kcrJ. SU. I: S. A. 91.
XOI-!-80016
25 Harmon.C.S. and Nc\ins;..f.D. ( Io()Z~ IL-la inhibitshumrnhair foliiclr growth
and hair fiber productioc; in whole-organculiures.Lw~~~/~ohrCl rdmt~I&.
I?. I97-103
26 Goldnw. C.K.. Tw. J.-C.. Sorowanu. L. and G~lleq~r. G.Y. ( I Wf; I 1,~sof
vascularendotheliilgrowthfactor in human alopecia hair follicles, J. hwr.
Demrcrtol.IO4 I SS-20s
27 J~tworsl\y.C. I 109sI Dermatopatbolngy of hair. in I)c)nrrcrlo~~,~~/llltc~/~~,~~
(Murphj.
G.F..cd. ). pp. 37 l-393. W.B. Saunders
28 Vassar.R. und Fuchs. E. ( 1991) Transgenicmiceprovidenew insightsinto Ihe
role nf TGF.a duringepidermaldevelopment and differentiation, CY~ Dtv
s, 714-727
29 Lueueke. NC. t~(11.( lY94 The mouse t1we&2 phenotype resultsfrum a point
mutationin (he KGF receptortyrosinekinase.GnrrsDt<c8.399-l I3
3u Guo. I... Yu. Q-C. and Fuchs, E. (1993) Targetingrwpressiua of kerutinucyre
growthfucturto kerutinocytcs elicitsstrikingchrmges in epirhcliuldiffwentia-
lion in transgenicmice,EhffNIJ. IZ!.Y73-986
Wsrnrr, S. (I ok ( l99.l) The Rnctiun of Kt;l: In mctrplrttgeursis trf cpitbelium
mJ r~~pi~belialiration of wounds.SUPUC t 2hhHItb42Z
JIIUCI~~~,J.J.,WOIQ,G,tl.N. imdYUIII~, A A. I IYOI) I~tlthuki~ I ~t~~it!~l~It~~tt
c~iosb~ antbiuonid~iltduccd uloprsiuiu thr rut urtrdcl,0Sl:H I 5, 4% ?I%+
IJimenez,J.J. nndYunis,A.A. (1992) Protectionfront I~P*D~srabinofuranc~cy.
tusine&ducedulopeclaby epidermulgrowth factsr and fibwblantgrowth
factorin the rat model,CnnccPr Res. 52,4 13-4I$
34 Anderson, T.D., Arcco, R. and Heycs,T.J. (1993) Comparativets%leiIyand
pathologyassociated wifb administrationof recombinantHull~ln to anlnialr,
in /rt/crnatio~a/ Reriew of Evperwret~rul&~Mo~,v (Vol. 34A 1t Richter.
G.W..
Solez, K. and Ryffel. B.. eds), pp. 9-36. AcademicPress
35 Tcrrell. T.G.. Working. l?K.. Chow. C.l? and Green. J.D. (I9931 Pathalqy of
recombinanthuman transforminggrowth factor+1 in ruts and rabbits. in
ittren&otud Review of Erperiwnrcrl &rhlogv (Vol. 34131(Richter.G. WC.Solez,
K. uud Ryffcl. 8.. cds). pp. 43-67, Ac:adanicPress
36 Weiner.N. CI fJ/. ( 1989) Topicaldeliveryof liposomallyencapsulated
interferon
evaluated in a culanrous herpes guinea pig model. AnIirnicr~~~. &otfs
elr~marlro:33, I2I7- I22I
37 Mitrqptri. S.. Bkmkschwin. D. and Lutger. R. (19%) Ultrasound-mediated
tran&rmal proteindelivery.Limc~ 260.850453
38 ~&;ui. A.L. et u/. (1994) Protectionagainstdoxorubicin=induced a@eciu in
ratsby liposome=entrapped monoclonal antibodies.FASEBJ. 8.22~230
39 ~j. L. ;mdHoffman.R.M. ( lc)9s)The feasibiliryof targetedselective
genetherapy
of tbe huir follicle.Nur.Med. 1.705706
40 Sun.W.H. pl nl. (1995) In vivagene transfer by genegun reducesMm
growthin mice.Pmt. Nut/. Acad. Sci. U. S. A. 92.28X9-2893
-
467