Hung-Yi Su

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Insulin-like growth factor 1 and hair growth
Hung-Yi Su,1,2 Jonathan G.H. Hickford,2 Roy Bickerstaffe,2 and Barry R Palmer2
Dermatology Online Journal 5(2):1

1 Division of Molecular Neurobiology, University of Cincinnati College of Medicine, P.O. Box 670559, Cincinnati, OH 45267, USA; 2Animal and Food Sciences Division, P.O. Box 84, Lincoln University, Canterbury, New Zealand

Abstract

Insulin-like growth factor 1 (IGF-1) has been identified as an important growth factor in many biological systems.[1] It shares considerable structural homology with insulin and exerts insulin-like effects on food intake and glucose metabolism. Recently it has been suggested to play a role in regulating cellular proliferation and migration during the development of hair follicles.[2,3] To exert its biological effects, the IGF-1 is required to activate cells by binding to specific cell-surface receptors. The type I IGF receptor (IGF-1R) is the only IGF receptor to have IGF-mediated signaling functions.[1] In circulation, this growth factor mediates endocrine action of growth hormone (GH) on somatic growth and is bound to specific binding proteins (BPs). The latter control IGF transport, efflux from vascular compartments and association with cell surface receptors.[4] In tissues, IGF-1 is produced by mesenchymal type cells and acts in a paracrine and autocrine fashion by binding to the IGF-1R. This binding activates the receptor tyrosine kinase (RTK) that triggers the downstream responses and finally stimulates cell division.[5] IGF-1 may therefore be able to stimulate the proliferation of hair follicle cells through cellular signaling pathways of its receptors.

Local infusion of IGF-1 into sheep has been reported to be capable of stimulating protein synthesis in the skin.[6] It may also increase the production of wool keratin. Recently, transgenic mice overexpressing IGF-1 in the skin have been shown to have earlier hair follicle development than controls.[7] In addition, this growth factor plays an important role in many cell types as a survival factor to prevent cell death.[8] This anti-apoptotic function of IGF-1 may be important to the development of follicle cells as follicles undergo a growth cycle where the regressive, catagen phase is apoptosis driven. In this review, the effects of IGF-1 on follicle cell proliferation and differentiation are discussed. In particular, the paracrine versus endocrine action of IGF-1 on hair growth and the targeting of expression of the growth factor to the follicles of transgenic animals will be emphasized. The anti-apoptotic role of IGF-1 in hair follicles is also reviewed. Prospects for future studies on hair and fiber growth by IGF-1 are discussed.

IGF-1 as a mitogen and morphogen

Mammalian hair growth is a dynamic process that depends on the proliferation, differentiation and migration of epithelial matrix cells within the bulb of the follicle.[9] DNA synthesis and keratinocyte growth have been reported to increase after the exogenous administration of IGF-1 to cultured human epidermis.[10] Mice with disrupted IGF-1R have a thinner epidermis and fewer keratinocytes compared to their control litter mates.[11] In addition, IGF-1R and BPs have been found in the dermis and the epidermis, although IGF-1 is only produced in the former.[12-15] It has, therefore, been speculated that (1) the dermal production of IGF-1 may participate in epidermal cell proliferation in a paracrine fashion, (2) the BPs and IGF-1R may play a role in transporting and binding IGF-1 from the dermis to epidermis and (3) IGF-1 may act as a mitogen in the development of skin.

Types of expression	Main cellular origins	References
IGF-1	Dermal Papilla	Messenger et al[23] Little et al[24] Itami et al[59]
IGF-1	Germinative matrix cells	Rudman et al [30]
IGF-1R*	Dermal papilla	Little et al [22] Dicks et al [20] Rudman et al [30]
IGF-1R*	Germinative matrix cells	Stones et al [19] Hodak et al [14] Dicks et al [20] Nixon et al [21]
IGF-1R*	Suprabasal matrix cells	Rudman et al [30]
BPs**	Dermal papilla	Batch et al [35] Hembree et al [36]

Table 1. Expression of IGF-1, its receptor and binding proteins in hair and wool follicles. *IGF-1R, IGF-1 receptors or type I IGF receptors **BPs, IGF binding proteins.

The proliferative function of IGF-1 in skin may be important to the development of hair follicles. A follicle consists of epidermal parts (the matrix and outer root sheath) and dermal components (the papilla and dermal sheath). Follicle development is a complex process which includes proliferation of the germinative matrix cells within the base of the follicle (the bulb) and their subsequent differentiation, keratinization and migration into different follicle cell layers. The dermal papilla has been thought to play an important role in the induction of germinative epithelial proliferation and the maintenance of hair growth.[16-18] IGF-1 may be involved in any one of these functions and may affect the development of follicles through the dermal papilla. Evidence has shown that IGF-1, its receptor and BPs are expressed in the papilla (Table 1). The receptor has been characterized from the germinative matrix cells of human, goat and ovine follicle bulbs [14,19-21] and its protein is differentially expressed in these cells through the hair cycle.[19,22] It is, therefore, thought that the papilla-produced IGF-1 may have paracrine effects on the growth of epithelial matrix cells.[23,24] However, studies on the paracrine/autocrine actions of locally produced IGF need to take into account systemic IGF-1, as the majority of IGF-1 distributed to tissues is from plasma.[25]

Types of expression	Main cellular origins	References
IGF-1	Dermal Papilla	Messenger et al[23] Little et al[24] Itami et al[59]
IGF-1	Germinative matrix cells	Rudman et al [30]
IGF-1R*	Dermal papilla	Little et al [22] Dicks et al [20] Rudman et al [30]
IGF-1R*	Germinative matrix cells	Stones et al [19] Hodak et al [14] Dicks et al [20] Nixon et al [21]
IGF-1R*	Suprabasal matrix cells	Rudman et al [30]
BPs**	Dermal papilla	Batch et al [35] Hembree et al [36]

Table 1. Expression of IGF-1, its receptor and binding proteins in hair and wool follicles. *IGF-1R, IGF-1 receptors or type I IGF receptors **BPs, IGF binding proteins.

Systemic IGF-1, whose expression is influenced by GH and nutrients, mediates the endocrine actions of GH but this effect may not extend to remote peripheral tissues such as skin or hair follicles. For example, Cottam et al [26] found no effect of systemic IGF-1 on wool growth despite an increase in plasma IGF-1 following an 8-week systemic infusion of IGF-1 into animals. Spencer et al [27] reported similar findings after the injection of recombinant GH into lambs. Adams et al demonstrated that the rate of wool growth was independent of plasma IGF-1 since wool growth rates remained unchanged following a reduction in plasma IGF-1 after undernourished animals were immunized against GH-releasing hormone.[28] After a period of re-feeding, both control and immunized animals showed similar wool growth rates despite differences in their plasma IGF-1 levels, confirming that systemic IGF-1 is not an important determinant of wool growth.[29] In summary, studies on sheep have revealed that the endocrine role of IGF-1 is probably not important to hair fiber growth.

Recent evidence suggests that IGF-1 may affect hair follicle morphogenesis, as differentiating matrix cells are shown to express IGF-1R during development of follicle cells.[30] IGF-1 may therefore have dual function, acting as a mitogen and morphogen in follicle development.

The dual proliferative and differentiative role of IGF-1 in follicles may be achieved by cellular signaling through its interaction with IGF-1R and BPs. For example, a ligand-receptor complex is formed to activate cells when IGF-1 binds to its receptors on the cell surface. The receptors consist of three regions: a short extracellular domain which binds to IGF-1; a transmembrane domain; and a large intracellular domain.[5] Ligand-binding of two neighboring receptors or subunits of the extracellular domain induces conformation changes in the intracellular domain, triggers a series of intracellular phosphorylations and leads to an initiation of DNA synthesis and cell proliferation. These intracellular biochemical reactions are mostly regulated by tyrosine kinases that phosphorylate cytoplasmic proteins. The latter migrate to the nucleus in which they activate specific genes. Recently, Eicheler et al demonstrated that protein kinase C (PKC) levels were unchanged in the papilla after exogenous administration of IGF-1 in culture, implying that signal transduction pathways through IGF-1 may not occur in the papilla.[31] IGF-1 has been reported to have an increased effect on the growth of cultured hair follicles.[32] Therefore, the findings by Eicheler's group suggest the stimulation of follicle growth by IGF-1 occurs in the other follicle cells but not papilla.[31] This idea supports the paracrine role of papilla-derived IGF-1 in the proliferation and differentiation of the surrounding epithelial cells.[23,24]

The role of BPs in hair follicle growth is not fully understood, but they may potentiate IGF's action by bringing it to the proximity of IGF-1R or inhibit its action by binding free IGF-1 and sequestering it from the IGF-1R.[33-35] Several BPs have been identified in the follicles [35] and, in particular, the papilla produced BP-3 has been reported to be increased by administration of exogenous IGF-1.[36] It is possible that, when IGF-1 is present at high concentrations, an increased production of BPs in the papilla occurs and this changes the interaction between BPs, IGF-1R and IGF-1. The latter modulates IGF's action on the follicle cell proliferation and differentiation.

IGF-1 as an anti-apoptotic factor in hair cycle

The growth of hair is a cyclic process in which every follicle proceeds from an active phase (anagen) through a regression phase (catagen) to a resting phase (telogen). During catagen, the follicle shortens through a process of programmed cell death (PCD) and apoptosis.[37] Apoptosis refers to the characteristic morphological changes found in PCD which include deletion of single cells, cell shrinkage and compaction of chromatin.[38,39] IGF-1 has been suggested as an anti-apoptotic survival factor in many cell types and may inhibit cell death during the catagen phase of the hair cycle.[8] Evidence has shown that IGF-1 is essential for the maintenance of follicle growth in the hair cycle anagen phase [34,40] and the receptor mRNA is down-regulated on the onset of the catagen phase.[22,30] Several domains of IGF-1R were also found to possess its protective function from apoptosis.[41] For example, receptors mutated at different tyrosine clusters within the kinase domain are capable of suppressing apoptosis, while these mutations are not able to activate cell transformation and proliferation. Results from C-terminal point mutations of the receptor show distinct anti-apoptotic functions, while removal of the entire C terminus has enhanced cell survival function and mitogenic activity.[41] In the latter case, the transformation function of the cultured cells is inactivated. These results suggest that domains of IGF-1R required for protection from PCD are different from those for mitogenic and transforming functions, and domains of the receptor required for apoptotic inhibition are necessary but not sufficient for transformation. It is possible that different domains of its receptor mediate control of hair growth through IGF-1 which performs distinct anti-apoptotic function on the growth of follicle cells. The effect of IGF-1 on the hair cycle has been thought to be an anagen extension and catagen inhibition and this may be due to the anti-survival function of different domains in the IGF-1R. The latter function may be insufficient to have any effect on follicle cell proliferation and transformation. This idea is supported by the findings of Resenicoff et al[42] who demonstrated that the baculovirus anti-apoptotic p35 protein has transforming potential only when IGF-1R is present. It is possible that, when IGF-1R is low in concentration, the increased activity of PCD and reduced activities of cell proliferation and transformation cause follicle cells to regress into the catagen phase.[22,30]

Expression of several apoptosis-related genes has been studied in different stages of the hair cycle and here particular attention is drawn to two proto-oncogenes, bcl-2 and c-myc, due to their regulation by IGF-1.[37,43] For example, bcl-2 was found in the dermal papilla throughout the murine hair cycle, but its expression in the follicular epithelium increases in anagen, decreases in catagen and disappears in telogen.[43] Lindner et al[44] also demonstrated that during catagen, follicle cells in the bulb region undergo apoptosis and this is correlated with a down-regulation of bcl-2, while these apoptotic processes do not occur in the dermal papilla. Similar findings were reported for c-myc expression in the murine hair cycle.[37] It has been thought that changes in the expression level of bcl-2 and c-myc genes before catagen may be signals for the apoptotic mechanism, while their reduced expression during catagen may be due to the apoptotic process.[37] Further, the findings that bcl-2 is expressed in the papilla throughout the cycle suggest that the papilla is involved in the expression of anti-apoptotic genes and protected from PCD during the hair cycle.[43]

The regulation of bcl-2 and c-myc through IGF signaling pathways has been studied in other cell types. For example, apoptosis prevented by IGF-1 in promyeloid cells during aging was reported to be associated with an activation of the phosphatidylinositol 3'-kinase (PI 3-kinase).[45] The latter function is correlated with the high levels of bcl-2. In brains, hypoxia-induced neuronal cell death can be inhibited by administration of IGF-1 and this is due to a down-regulation of the anti-apoptotic protein, bcl-2.[46] Further, the induction of apoptosis by c-myc in embryonic fibroblasts was demonstrated to be suppressed by IGF-1 through a pathway mediated by the cell surface receptor, CD95.[47] It is possible, however, that hair cycle-dependent expression of bcl-2 and c-myc in the follicles is regulated by IGF-1 through different signal transduction pathways.

IGF-1 as an anabolic mediator

Hair growth is a process in which the biosynthesis of a complex mixture of proteins is involved. Hair fibers are mainly composed of cortex and cuticle cells which synthesize low-sulphur intermediate filament (IF) proteins whilst the hair matrix produces high-sulphur (HS) and high-glycine/tyrosine (HGT) intermediate filament associated proteins (IFAPs).[9] The HS proteins, which are rich in cysteine, provide a chemical means to cross-link the intermediate filaments of epithelial cells. Ultra-high-sulphur (UHS) proteins, a sub-group of HS proteins, have the highest cysteine content of all animal proteins and are expressed only during the anagen phase of the hair cycle. The anabolic effects of IGF-1 on protein synthesis in animals have been studied using different stimuli such as fasting [48,49], nitrogen restriction [50] and diabetes.[51] Results from these studies demonstrated that the systemic administration of IGF-1 to such animals produced whole-body protein-conserving effects by reducing protein degradation and accelerating protein synthesis in tissues. In well-nourished lambs, Oddy and Owens also demonstrated that protein degradation is reduced in the hind limbs of animals after the peripheral infusion of IGF-1.[52]

It has been speculated that IGF-1 may have a similar protein-conserving effect on skin, if administered locally, and may affect hair fiber growth. To test this hypothesis, one research group has extensively investigated the role of IGF-1 in the metabolism of ovine skin.[6,53,54] They demonstrated that the short-term (within 24 hours) infusion of a long-acting IGF-1 (LR3IGF-1) increased skin blood flow and the net uptake of cysteine and tyrosine but there was no change in wool bulb replicating cell numbers. They suggested that the local administration of IGF-1 has no influence on follicle growth.[6,54] However, the duration of the short-term infusion may have been insufficient to stimulate cell proliferation. It is, therefore, difficult to assess the significance of the results in term of longer-term effects on protein pools in the skin and on wool production.

Hocking Edwards et al[53] extended the IGF-1 infusion period to 3 weeks and investigated skin protein metabolism within this period. They reported that after 2 days of LR3IGF-1 infusion as a result of increased protein degradation, both blood flow and the total uptake of phenylalanine by the skin were decreased to pre-infusion levels. They suggested that the increase in protein synthesis within 24 hours of IGF-1 infusion is transient and this probably accounts for the lack of an effect on wool production after 3 weeks of IGF-1 infusion.[53] Lobley et al[54] subsequently concluded that strategies based on repartitioning protein synthesis to skin by the local infusion of IGF-1 are unlikely to produce persistent anabolic responses or to have any influence on hair fiber growth. Although this conclusion seems logical, the regulation of follicle growth through IGF-1 may involve other factors. For example, Hembree et al[36] reported that stimulation of BP production, by the injection of exogenous IGF-1, can modulate the action of IGF-1 on hair elongation in vitro. Infusion of IGF-1 into sheep skin may not only change the local production of BPs but also its interaction with IGF-1R.[6,53,54] The latter may change the binding of the growth factor to follicle cells, modulate its action on the proliferation of epithelial matrix cells and affect fiber growth. It would be interesting to determine if the expression of BPs and IGF-1R is changed in IGF-1 infused animals and to assess whether there is an association with the observed phenotype. It would also be interesting to assess from histological studies the cellular location of infused IGF-1 in the wool follicles. This may provide an insight into determining whether exogenous IGF-1 has any association with the proliferation of epithelial germinative cells in the wool bulb.

IGF-1 and androgen

Human hair follicles are targets of sex steroids. In particular, androgens induce regression of terminal (large) hair during the development of male-pattern baldness and transform vellus (small) hair to terminal hair in genital skin during puberty.[55] These effects may be associated with high levels of circulating IGF-1 [56] which directly stimulates the activity of the androgen receptor.[57] It is also possible that IGF-1 stimulates the activity of 5-reductase in the skin which increases the local production of dihydrotestosterone converted from testosterone.[58]

The mechanisms by which androgens stimulate hair growth are not fully understood but may be mediated by IGF-1 from the dermal papilla. For example, Itami et al [59] demonstrated that androgens are capable of stimulating proliferation of the beard papilla cells but not the outer root sheath (ORS) cells. However, when ORS cells are cocultured with the papilla cells without cell contact, androgens are able to stimulate their growth. In addition, they found that IGF-1 mRNA is expressed in the papilla but not in ORS and suggested the proliferation of ORS cells in androgen-induced hair growth is mediated by IGF-1 from the papilla.[59]

In summary, regulation of human hair growth by androgen is probably mediated by IGF-1 in the dermal papilla. In male scalp, high levels of IGF-1 may increase the androgen receptor activity and dihydrotestosterone levels and these result in an increased propensity for baldness.

IGF-1 transgenic animals

Early studies of IGF-1 transgenic animals were designed to investigate the effect of IGF-1 on somatic growth using a metallothionine promoter. Overexpressed IGF-1 produced both endocrine and paracrine/autocrine effects on mouse growth.[60,61] Recently, IGF-1 transgenic sheep [62] and mice [63] were produced using a mouse ultra-high-sulphur keratin (UHS-KER) gene promoter to target transgene expression to the wool and hair follicles. Phenotypic effects on fiber growth from one of the transgenic lines in sheep and mice are summarized and discussed below.

In sheep, clean fleece weight increased during yearling shearing in transgenic animals compared to their non-transgenic half-sibs.[62] The increase was not observed in the second year [64] which is probably due to reduction of IGF-1R in the skin and wool follicles in the second year. This is supported by Werner et al,[65] who observed that rat IGF-1R mRNA levels in liver, brain, stomach, muscle, kidney and heart of rats decreased with increasing age from birth to 7-weeks. In sheep, the binding of IGF-1 to some skeletal muscle cell types and to kidney cells has also been shown to decrease with the increase in age of animals from 6 months to 2 years.[66,67] It has been speculated that IGF-1 plays an anabolic, rather than growth-promoting role in older animals.[68] The decline in receptor abundance in the tissues of older animals correlates with the decrease in growth rate. Thus, it is feasible that the reduction in the abundance of IGF-1R levels in the skin and wool follicles in the second year is due to the reduction in binding of the transgene to receptors. This is consistent with the age effect and the associated reduction in clean wool weight in year 2. To confirm the effect will require a comparison of the IGF-1R levels in animals in year 1 and year 2 in order to determine whether there is an age effect on transgene expression on wool growth.

In IGF-1 transgenic mice, we have demonstrated that vibrissa elongation is significantly increased during the first neonatal hair cycle compared to their litter mates.[63] The expression of IGF-1 mRNA in the keratogenous zone of transgenic mice may cause an increased level of IGF-1 peptide which diffuses to the follicle bulb and exerts a paracrine effect on the proliferation of epithelial matrix cells. This results in the observed phenotypic effects on vibrissa growth.[63] Confirmation of the effect will require in situ hybridization to detect the sites of transgene IGF-1 expression within the follicle and to determine the mechanism of the paracrine action.

IGF-1 may also affect fiber characteristics through its action on follicular metabolism. In transgenic sheep, there was a significant increase in fiber diameter compared to the non-transgenic animals.[64] The infusion of IGF-1 into the skin of sheep has been shown to increase local blood flow, oxygen utilization and cysteine uptake.[6] In our study, overexpression of the transgene may stimulate follicular metabolism and, as a consequence, enhance cysteine uptake and increase the proportion of paracortex cells in the wool fiber [69] which, in turn, is associated with larger diameter fibers.[70] The increase in fiber diameter may result in an increase in fiber growth in IGF-1 transgenic sheep [64], although confirmation of the effect of IGF-1 on fiber diameter will require data from other transgenic lines of sheep.

Summary and future work

IGF-1 has been reported to increase hair follicle growth in vitro.[32] However, in vivo studies do not support the in vitro results. Results from our unpublished data show that the systemic administration of exogenous IGF-1 during the anagen phase of murine hair cycle has no effect on vibrissa growth. Other in vivo results have also shown that there is no effect of IGF-1 on wool growth whether introduced systemically [26] or locally [53] over a long period of time.

IGF-1R may play a key role in the regulation of hair growth. Liu et al[11] demonstrated that IGF-1R knockout mice have significantly fewer, smaller and more widely spaced follicles than controls, although some of the animals die shortly after birth or show a growth deficiency. The precise mechanisms by which IGF-1R regulates follicle growth is not fully understood but they probably act on epithelial proliferation/differentiation [30] and on catagen inhibition/anagen extension.[22]

As mentioned previously, IGF-1 appears to have no in vivo effect on hair growth. In addition, there is growing evidence that IGF-1R is involved in follicle growth but no in vivo studies have, as yet, demonstrated that IGF-1R regulates hair growth. It is, therefore, important to perform both systemic and local administration of IGF-1R in order to determine its role in the growth of hair follicles. Transgenic approaches [62,63] appear more promising than traditional IGF-1 administration [26,53] as the existing data suggest that transgenic animals produce more hair fibers than controls. Future studies are needed, however, to produce IGF-1R transgenic animals, IGF-1R/IGF-1 double transgenic animals and null mutated IGF-1R (IGF-1Rmut) transgenic animals to compare the phenotypic effects of the transgenic and control animals on follicle growth.

Conclusion

Control of hair growth through IGF-1 involves BPs which control IGF transport, efflux from the circulation and association with IGF-1R. The regulation of follicle growth through IGF-1 is due, therefore, to the interaction of circulating and locally produced IGF-1 on the hair follicles. It can be concluded that studies on the effects of IGF-1 on hair growth should, in future, concentrate on the associated changes in the BPs and IGF-1R in the circulation and in the follicle.

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© 1999 Dermatology Online Journal

Insulin-like growth factor 1 and hair growth Hung-Yi Su,1,2 Jonathan G.H. Hickford,2 Roy Bickerstaffe,2 and Barry R Palmer2 Dermatology Online Journal 5(2):1