Growth factors in early hair follicle morphogenesis

ARTICLE

Hair follicle embryogenesis involves embryonic epidermis and mesenchyme communication on several levels, utilizing cell surface receptor expression, cell adhesion molecules, extra cellular matrix products, and chemical signaling via secreted molecules. With each product involved in cell communication, intensity, potency, time of production during development, production duration, and spatial distribution must all be considered. The sum of these factors in a regulated expression sequence order [1] must provide adequate information to embryonic cells about their respective location and role within the developing hair follicle. Cell communication is required for appropriate spatial distribution of hair follicles through the skin, location of hair follicle subtypes in the relevant body map position, and development of different hair follicle subtypes (terminal, vellus, cilia, etc).

Classic studies show the embryonic epidermis and mesenchyme must communicate to form a hair follicle. Studies involving grafting of mismatched dermis and epidermis show the dermis defines hair follicle size, shape, and distribution [2]. Confirmation of soluble factor communication between the hair follicle dermal papilla (DP) and epidermal cells is demonstrated by the use of DP cell conditioned medium to stimulate epidermal keratinocytes [3]. Most significantly, DP cells have the ability to induce new hair follicle development from epidermis, even in adult mammals [4, 5]. Epithelial down growth and differentiation in association with an aggregation of mesenchyme derived dermal cells is also observed in tooth, nail, and feather morphogenesis. This suggests similar signals between the mesenchyme and epidermis may be involved in hair follicle, tooth, nail, and feather development [6, 7].

The description of the dynamic morphology of cell migration and differentiation within hair follicle embryogenesis has been comprehensively addressed [8-14]. Expression of molecules known to be associated with mature hair follicle growth and cycling are reviewed elsewhere [15, 16]. Here we review known growth factors and receptor expression patterns during early hair follicle embryogenesis.

Growth factors expressed during hair follicle morphogenesis

Many published studies examine growth factor expression at a specific time point during embryogenesis and may not cover the complete developmental process. Those studies that do examine expression throughout hair follicle embryogenesis may use different definitions for embryonic ages and hair follicle embryogenesis stages, making it difficult to compare and contrast results from different investigators.

The different tissue sources, variations in the rate of embryogenesis for different species, the arbitary imposition of distinct time stages on what is a continuous embryogenic development process and the different hair follicle types examined, illustrate that a degree of interpretation has been used by the reviewers to identify and standardize the development stages and distribution of molecule expression within embryogenic hair follicles described by different research groups. For the purposes of this review, hair follicle development was divided into eight stages, similar to a recent description [14] and as elucidated in Figures 1 and 2.

Transforming growth factors

The transforming growth factor beta (TGFbeta) family includes many structurally related proteins that have been implicated in numerous cellular processes. The beta type transforming growth factor isoforms comprise TGFbeta1-TGFbeta4 of which the first three have been shown to be expressed during tooth embryogenesis [17, 18] and hair follicle morphogenesis (Table I).

For any secretory product to have an influence on cells, the cells must express appropriate receptors. TGFbeta1 and TGFbeta3 both bind to TGFbeta receptor type II (TGFbeta-RII). To initiate the downstream signaling process TGFbeta-RII must then complex with TGFbeta-RI. For a cell to receive a TGFbeta1 or TGFbeta3 signal it must co-express both TGFbeta-RI and TGFbeta-RII [19]. Onset of TGF receptor expression occurs very early in hair follicle morphogenesis with TGFbeta-RII present in stage one of development [14, 19].

Over-expression of TGFbeta1 restricted to the epidermis in transgenic mice results in suppression of epithelial cell proliferation, reduced hair follicle development, and severely curtailed life span [20]. By contrast TGFbeta1 null mice survive to adult hood and show only a slightly reduced number of hair follicles [21]. TGFbeta2 null mice die at the time of birth and have a reduced density of hair follicles in pelage skin, but TGFbeta3 null mice show no apparent hair follicle defects [21]. Overall, data suggest that TGFbeta family members play a role in follicular development and cell proliferation inhibition [22].

Inhibins and activins are members of the TGFbeta super-family and have been suggested to act as paracrine, endocrine, and autocrine regulators present in a range of tissues [23]. These factors are likely candidates for playing a significant role during hair follicle morphogenesis although thus far there has been limited research to identify inhibin or activin involvement. The activin betaA subunit has been identified as important for tooth morphogenesis and is expressed in mesenchymal tissue [24]. Activin betaA is known to be expressed in the hair bulb of embryonic rat vibrissae and hair follicles [25] although the specific expression distribution was not defined. Mice lacking the activin betaA gene show normal vibrissa pad development but do not produce hair fibers [26] and mouse mutants deficient in the activin antagonist follistatin show significant whisker and tooth abnormalities [27]. Such mutant mice die shortly after birth and so the effects on pelage hair have not been detailed.

Bone morphogenic proteins

Bone morphogenic proteins (BMPs) are also related to the TGFbeta super-family. As the name suggests, BMPs were originally implicated in cartilage and bone formation. Expression of BMPs have now been observed in many tissues undergoing morphogenesis and have been suggested as regulators of ectodermal-mesenchymal interactions. Eight BMP variants have been identified to date. BMP1-BMP7 have been associated with tooth development [28-31] and size and spatial distribution of feather buds [32] indicating a potential role for this factor family in hair follicle development.

BMP2-BMP4 and BMP7 expression have been identified in developing hair follicles (Table I) [33]. BMP4 is the first growth factor expressed in advance of dermal condensation development, although expression is transient [34]. BMP6 (Vgr-1) has no apparent gene expression in any stage of hair follicle embryogenesis [35, 36] indicating not all BMP family members are involved in epidermal appendage development. BMP receptor expression in hair follicles has received limited attention so far. BMP2/4 type I receptor is known to be expressed during hair morphogenesis [37], but expression of other BMP receptors within hair follicles is unknown.

Mice with a BMP7 null mutation have numerous defects but apparently develop a normal pelage coat [38]. However, over-expression of BMP4 results in inhibition of outer root sheath (ORS) and matrix cell proliferation [39] in similar fashion to observations made in mice with over-expression of TGFbeta1 [20]. Circumstantially, the evidence suggests BMPs and their receptors may be important in directing hair follicle embryogenesis.

Epidermal growth factors

The epidermal growth factor (EGF) family contains several signaling molecules that may be important in hair follicle development as the EGF family is closely associated with keratinocyte growth. EGFs are produced by keratinocytes and provide paracrine and autocrine stimulation. EGF has been associated with epidermal appendage development since its initial discovery as a stimulator of tooth development and isolation from saliva [40]. As a promoter of epithelial cell growth, it may also play an important role in hair follicle embryogenesis.

Research on the expression of EGF and EGF-R in hair follicle embryogenesis has been conducted using a variety of tissue sources from sheep [41], rodents [42, 43], and humans [44]. EGF and its receptor EGF-R have been identified in regions of epidermal cell proliferation and also in less mitotically active differentiating cells of the embryonic hair follicle. In general, EGF-R has been identified in a similar expression pattern to EGF but with a more extensive tissue distribution within the hair follicle. It is commonly agreed that EGF and EGF-R are expressed from the earliest stages of epidermis development, but are only expressed in the later stages of developing hair follicles [45]. Some report uniform EGF and EGF-R expression throughout the periderm at the time of initial hair follicle embryogenesis in basal and suprabasal cell layers [41], others indicate reduced expression of EGF-R in epidermal cells overlying the hair germ [42]. Later stages of follicle maturation show EGF and EGF-R expression, but the specific stage for the onset of initial hair follicle expression is open to question, given the different results of various studies [41, 42, 44]. Mature hair follicles continue to express EGF-R in the ORS [46].

Injection of EGF promotes epidermal thickening and inhibition of hair fiber growth [47]. EGF-R mutations in mice have been noted to involve hair defects. Mutations of X-linked genes in Tabby mice have been linked with the EGF signal pathway and abnormal hair follicle development [48] and Waved-2 mouse mutants have a point mutation of tyrosine kinase in the EGF-R gene. Mice dominant negative for EGF-R in the epidermis show short and waved pelage hair shortly after birth with gradual development of extensive alopecia in adult life associated with skin inflammation [49]. Skin from EGF-R null mice grafted to nude mice show extensive hair follicle dystrophy and an inability to enter telogen [45]. There is a likely epistatic relationship between EGF-R and FGF5 in hair follicle development and cycling as demonstrated by cross breeding of mouse mutants [50].

TGFalpha is an EGF family member and may also play a role in hair follicle development. Although the initial onset of expression during hair follicle embryogenesis is not known, several differentiating cell subsets express TGFalpha (Table I). EGF-R can be the receptor for both EGF and for TGFalpha [51]. TGFalpha over-expression in the epidermis of transgenic mice leads to stunted dystrophic hair growth [52, 53]. Mice with a null mutation of TGFalpha have dystrophic hair follicles producing a pelage of waved hair equivalent to the spontaneous Waved-1 mouse mutation [54].

Amphiregulin is a member of the EGF family and is a known growth factor for keratinocytes. Transgenic mice with expression of amphiregulin in basal keratinocytes yield a phenotype including psoriatic lesions and alopecia [55]. Other members of the EGF family include betacellulin, epiregulin, and heparin binding epidermal growth factor (HB-EGF). HB-EGF expression has been noted in the outer root sheath and sebaceous glands of adult human hair follicles [56].

Fibroblast growth factors

Fibroblast growth factors (FGFs) can influence the growth and differentiation of cells from both the ectoderm and mesoderm. Only cursory research has been conducted on the presence and significance of FGF family members and their receptors in hair follicle embryogenesis. The FGF family contains nine known members. FGF1 and FGF2, originally named acidic FGF and basic FGF respectively, have been identified in developing hair follicles along with FGF receptors 1 and 2, previously known as flg and bek respectively (Table I).

There is some evidence indicating that other FGF molecules may be involved in hair follicle development. FGF1-4 and FGF8 and 9 expression have been observed in tooth development [57-59], and FGFs 1, 2, 4, 5, and 7 have been positively identified in mature cycling hair follicles [60, 61]. The spontaneous mouse mutation, Angora, involves a sequence deletion in the FGF5 gene. Angora mice have very long pelage hair due to a prolonged anagen growth phase [62]. Mice homozygous for a null allele of the FGF5 gene are also reported with abnormally long hair [58].

Keratinocyte growth factor (KGF) is a member of the FGF family, also known as FGF7. It selectively promotes proliferation and differentiation of keratinocytes. FGF7 expression has been observed in adult hair follicles [61]. Transgenic mice with over-expression of FGF7 have a reduction in the number of developing hair follicles [62, 63] and mice deficient in FGF7 develop a normal hair density, but a progressively matted pelage coat [64]. This evidence, plus the knowledge that FGF1 and FGF2 are expressed during hair follicle embryogenesis, suggests the FGF family is worthy of further investigation for their importance in hair follicle development.

Neurotrophins

Initially, neurotrophic growth factors were identified as regulators of neuronal development, but the neurotrophin (NT) family is now known to have a wide range of functions. Neurotrophins and their receptors are expressed in many cells types including keratinocytes. Nerve growth factor (NGF), neurotrophins 3 (NT3) and 4 (NT4) and brain derived neurotrophic factor (BDNF) may all be expressed during hair follicle morphogenesis [65]. NT3 production begins late in embryogenesis with expression from stage 6 onwards in the ORS and some cells of the DP. With further development, NT3 expression persists in the ORS and expands to involve all DP cells [66]. NT3, NT4 and BDNF are most intensively expressed during the regression of mature hair follicles into catagen [66, 67].

There are several neurotrophin receptors that are expressed during hair follicle morphogenesis and some bind more than one neurotrophin. The low affinity receptor, p75NTR, will bind NT3, NT4, BDNF, and NGF. High affinity receptors are more exclusive in their binding properties. NGF binds with high affinity to tyrosine kinase receptor A (TrkA), BDNF and NT4 both bind with tyrosine kinase receptor B (TrkB), and NT3 binds to tyrosine kinase receptor C (TrkC). However, high affinity receptors may also be low affinity receptors for various neurotrophins [68]. TrkC, and p75NTR are expressed during one or more stages of hair follicle morphogenesis as well as during the adult hair cycle (Table I).

Transgenic mice with over-expression of BDNF showed truncated hair follicle cylces with short hair fiber growth whereas knockout mice showed reduced catagen regression [67]. NT3 null transgenic mice show delayed hair follicle morphogenesis, whereas NT3 over expressing transgenic mice show accelerated follicle morphogenesis [66, 67]. Mice deficient in NGF show limited hair growth suggesting truncated hair cycles and premature entry into catagen [69]. These apparent gross distinctions in transgenic mice and expression of several NT and neurotrophin receptors suggest an important role for neurotrophins in the development and cycling of hair follicles.

Platelet derived growth factor (PDGF)

Platelet derived growth factor (PDGF) is produced by many cells types including endothelial cells, keratinocytes and fibroblasts and PDGF is a known chemoattractant for fibroblasts [70]. PDGF-A, B, and their receptors, PDGFalpha-R and PDGFbeta-R, have been confirmed as present during hair follicle embryogenesis. Intriguingly, PDGF-A and PDGF-B are observed in the hair germ while the respective receptors are expressed in the DP [71-73], suggesting PDGFs may be important for epithelium-mesenchyme communication.

Blocking PDGFalpha-R with monoclonal antibodies during neonatal development stop the maturation of hair follicles, further supporting a communication role for PDGF during hair follicle differentiation [74]. Mice with a null mutation for Postnatal PDGF-A develop abnormal hair follicles with small dermal papillae and abnormal dermal sheaths [73]. PDGFs may have a role in regulating DP and dermal sheath development.

Hh gene products

The hedgehog (Hh) gene products are secreted and interact with cell receptor ligands and so may be described as growth modulating factors. Sonic hedgehog (Shh) was the first Hh gene to be identified in vertebrates [75] and has been shown to be present during feather, tooth, and hair follicle development [76-79]. Although the specific function of Shh in hair follicle embryogenesis has not been confirmed, it is believed that Shh is important in appendage orientation along with Wnt genes [1]. Shh proteins interact with a receptor complex that includes the transmembrane proteins Patched (Ptc) and Smoothened (Smo). Shh is believed to bind to Ptc1 and this then releases Smo from Ptc-mediated repression. Smo activity leads to transcription of Hh target genes utilizing Gli transcription factor proteins [80].

Mouse embryos with a Shh null mutation have hair follicle growth arrested after the initial stage of hair follicle development. Transplantation of skin from these embryos to nude mice results in severely dystrophic hair follicle development without hair fiber production [77, 78]. Injection of Shh cDNA into adult mice resulted in transient expression of the gene product and induced anagen in telogen stages hair follicles and onset of anagen in adult mouse hair follicles is associated with increased expression of both Shh and Ptc1 [81]. During hair follicle embryogenesis, Shh is first expressed in distinct regions of the epidermis where future hair follicles will develop. With down growth of the hair germ, Shh expression is limited to epithelium derived cells in close proximity to the DP [79]. Expression of Shh may be limited to the hair germ, but Ptc1 is expressed in both the hair germ and the dermal condensate [78]. Shh clearly has a significant role to play in the early events of hair follicle morphogenesis and may be involved in epidermis-mesenchyme signaling [78].

Wnt gene products

There are numerous Wnt genes and variants in different species although only 19 have so far been identified in mammals. Wnt genes encode small proteins that are secreted from cells and interact with cell surface receptors from the Frizzeled family. Wnt protein binding to a Frizzeled receptor activates a cascade of events within the cell that lead to signal transduction of beta-catenin and ultimate transcription of Wnt gene targets. The importance of the cascade of events downstream of Wnt protein signaling is illustrated by transgenic mice with activated expression of beta-catenin that undergo increased hair follicle morphogenesis [82, 83] resulting in a higher density of hair follicles than would normally be expected.

Over-expression of Wnt3 in the epidermis of transgenic mice results in a short hair phenotype, cyclical alopecia, and abnormal hair follicle differentiation [84]. Wnt4 null mice showed minor skin defects but normal hair growth was possible from Wnt4 null mouse derived skin when grafted to nude mice indicating not all Wnt genes are important for hair follicle development [85]. However, Wnt gene expression, including Wnt11 and Wnt7a, has been associated with feather development [1, 86, 87] and Wnt10a and 10b have been identified in developing tooth primordia [88]. Wnt genes may be significant in hair follicle morphogenesis and expression of Wnt10b has been confirmed in developing vibrissae follicles [89] although the description was not detailed enough to enable inclusion in Table I.

Interleukins

The interleukins (ILs) are a diverse collective of secretory factors most commonly associated with immune system function. Several interleukins and/or their receptors have been identified in hair follicles. Interleukin 1 receptor (IL-1R1) can be observed in stage two hair germs and persists in the ORS and matrix, but not in the IRS or DP [14]. IL-1beta is produced by DP cells from mature hair follicles suggesting a possible role for this cytokine in mesenchyme-epidermis communication [90]. IL-1beta expression has been reported in the IRS of mature hair follicles [91], and both IL-1alpha and IL-1beta expression is increased at the onset of catagen [92]. IL-1alpha and IL-6 expression has been shown in adult ORS and dermal sheath [91]. IL-1alpha over-expressing transgenic mice develop a skin disease that involves hair loss [93] and transgenic mice over-expressing IL-6 show reduced hair growth [94]. Local expression of interleukins and their receptors during hair follicle development have the potential to significantly influence follicle differentiation.

Other growth factors potentially involved in hair follicle embryogenesis

Several growth factors and their receptors that have yet to be identified in embryogenic hair follicles have been identified at different stages of the adult hair follicles cycle. Given that the mature hair follicle expresses embryogenic properties [95], these factors may potentially also be important in initial hair follicle development. Insulin-like Growth Factor 1 (IGF-1) mRNA has been identified in rat hair follicles [96, 97] and transgenic mice over expressing IGF-1 show accelerated hair follicle development [98] and increased vibrissae growth during the first hair cycle [99]. Sebocytes express tumor necrosis factor alpha (TNFalpha) [100], and transgenic mice with TNFalpha over expression targeted to the epidermis show retarded hair growth [101].

Vascular Endothelial Growth Factor (VEGF) may be important in hair follicle embryogenesis and development of appropriate capillary blood supply for the dermal papilla. VEGF is secreted in various cells including keratinocytes and fibroblasts. It may have a role in the adult hair follicle cycle where vascularization regresses as hair follicles enter catagen and regenerates during early anagen [11] and VEGF has been shown to be a growth factor for cultured DP cells and hair follicles [102-103]. VEGF is expressed in mature hair follicle IRS, ORS, and DP [104, 105].

Several other growth factors have the potential for involvement in hair follicle embryogenesis although there is no information on their expression in developing or adult hair follicles. Midkine (MK) has been suggested as important in the regulation of tooth development [106] where it is transiently expressed in both epithelium and mesenchyme. Glial cell line-derived neurotrophic factor (GDNF) is also expressed in epithelium and mesenchyme during tooth development [107] as is Hepatocyte growth factor-scatter factor (HGF-SF) and its receptor [108]. Hepatocyte growth factor (HGF) may be important for hair follicle morphogenesis. HGF has been shown to be expressed in DP cells and to have an anagen inducing effect in vivo and in vitro [109-111].

In summary, before a hypothetical sequence of growth factor induced events in hair follicle development can be put forward, there is an urgent need to identify all the potential factors that may be involved. This review may help with identifying candidate growth factors for further research. Subsequent considerations will include: the time sequence of expression and the location within the developing hair follicles, growth factor receptor expression time sequence and follicle location, the potential paracrine and autocrine actions of each growth factor, how the signaling activities of growth factors are modulated by extracellular and intracellular non-growth factors, and the potential for endocrine action by growth factors not produced in the immediate vicinity of embryogenic hair follicles.

Constantly cycling hair follicle morphology suggests a complex interaction between cells involving multiple gene expression patterns and biochemical interaction between cells at different stages of morphogenesis. The known expression of the growth factors described above circumstantially indicates their involvement in hair follicle embryogenesis. However, no growth factor acts in isolation in vivo. There are many non-growth factors that may control hair follicle development [15] and some may directly interact with growth factors. For example, the proteoglycan syndecan binds FGF2 [112]. Periodic expression of NCAM can be identified in mesenchyme condensations [113] and tenascin is expressed in the epithelium above the condensations in advance of epithelium proliferation and down growth [114]. Cultures of embryonic skin plus antibodies against E or P-cadherin resulted in abnormal hair follicle morphogenesis [115]. Adhesion molecules may therefore function to delineate distinct cell populations in early appendage development [116]. In addition, antagonistic regulatory molecules must be considered when examining the effects of growth factors on cells. Chordin, Noggin, Gremlin, Cerberus, and Dan are all secreted proteins that bind various BMPs and block their signaling [117]. There are many more such regulatory molecules that modulate growth factor activity within hair follicles.

When considering the effects of growth factors, the influence of the down stream molecular cascade must also be considered. Transcription factors for putative morphogens like BMP4 and EGF will be important in hair follicle embryogenesis. Homeobox-containing regulatory genes encoding transcription factors have been suggested to code for the hair follicle subtype and the orientation of the appendage [116]. Mice with a deficiency in the homeobox gene Hoxc13 develop to brittle hair and alopecia [118] and Wnt gene transcription factor beta-catenin is a key molecule in hair follicle induction [82, 83]. Lymphoid enhancer factor 1 (LEF-1) has been suggested as a hair specific keratin gene transcription factor based on sequence similarities [119]. LEF-1 was shown to be expressed in the ectoderm prior to dermal cell condensation and continued to be expressed in the hair follicle matrix cells and DP throughout hair follicle development [119]. Transgenic mice with increased expression of LEF-1 showed a number of hair follicle defects including delayed hair follicle development, irregular orientation, and spatial distribution of hair follicles [119]. Defining the contributions of various transcription factors to hair follicle development will be difficult.

Growth factors may be fundamental to mesenchymal-epidermal interactions, but they are clearly not the sole method of communication in early hair follicle embryogenesis. Few growth factors are expressed in advance of the visible morphological changes of mesenchymal cell condensation in the dermis and epidermal down growth. The initial activator(s) of hair follicle embryogenesis remain to be elucidated. Prior to the initial production of BMP2 and 4, as the first known growth factors to be expressed in hair follicle development [120], other potential morphogenic factors may appear. Incorporating all the various contributing factors into a single regulatory system of hair follicle embryogenesis will be very difficult although such hypotheses are being formulated [121]. Ultimately, the challenge to define the expression in space and time of growth factors, adhesion molecules, regulatory molecules, and transcription factors will have to be met before hair follicle embryogenessis can be fully understood.

Article accepted on 3/4/00

CONCLUSION

Acknowledgements

The authors would like to thank Dr J.P. Sundberg and Dr E. Levin for the critical review of this manuscript. This review was funded by a grant from the Ernst Schering Research Foundation (KJM) and the authors would like to thank the Schering Foundation for their support.

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