Effect of IGF-I on Hair Growth Is Related to the Anti-Apoptotic Effect of IGF-I and Up-Regulation of PDGF-A and PDGF-B

Background

Insulin-like growth factor-I (IGF-I) shares a high degree of structural and functional homology with insulin and is a potent mitogen supporting cell growth and survival in many kinds of the tissues and cells. It also plays a role in some differentiation and anti-apoptotic functions. In previous reports, it has been shown that IGF-I stimulates hair follicle (HF) growth, maintains the anagen stage, and postpones the catagen stage.

Objective

The exact mechanism of the effect of IGF-I on HF growth is not yet established. Therefore, we investigated the relationships between IGF-I and various other factors (i.e. apoptosis related molecules, pro-inflammatory cytokines, other growth factors, etc.) in the control of HF growth.

Methods

The effect of IGF-I on human hair growth was measured using an organ culture model of human HFs and compared with a control group that did not receive IGF-I. We also measured mRNA expression of factors related to hair growth and apoptosis (which was determined by reverse transcription polymerase chain reaction (RT-PCR). RT-PCR was done on days 2, 4, 6, and 8 of organ culture.

Results

In organ cultured human hair follicles, IGF-I had a positive effect on the rate of linear hair growth. IGF-I maintained the anagen phase. IGF-I increased the expression of platelet-derived growth factor (PDGF)-A, PDGF-B and the expression ratio of Bcl-2/Bax.

Conclusion

The effect of IGF-I on hair growth appears to be related to the upregulation of PDGF-A and PDGF-B and to the anti-apoptotic effect of IGF-I.

Insulin-like growth factor-I (IGF-I) is a growth factor with sequence homology to pro-insulin. It has been identified as an important growth factor in many biological systems1. IGF-I is critically involved in promoting hair growth by regulating cellular proliferation and migration during the development of hair follicles (HFs)2. The proliferating function of IGF-I in skin may be important to the development of HFs. Transgenic mice overexpressing IGF-I in the skin have earlier HF development3. IGF-I receptor knockout mice have fewer, smaller and earlier HF development4. Itami and Inui5 demonstrated that IGF-I is produced by dermal papilla cells. Since IGF-I receptors were detected in keratinocytes, it is possible that IGF-I produced by dermal papilla cells might act on keratinocytes, thereby promoting hair growth through stimulation of the proliferation of keratinocytes in the HFs6.

To exert its biological effects, IGF-I must activate cells by binding to specific cell-surface receptors. The type I IGF receptor (IGF-IR) is the only IGF receptor to have IGF-mediated signaling functions1. In tissues, IGF-I is produced by mesenchymal type cells and acts in a paracrine fashion and/or an autocrine fashion by binding to the IGF-IR. This binding activates the receptor tyrosine kinase that triggers the downstream responses and finally stimulates cell division7. IGF-I may therefore be able to stimulate the proliferation of HF cells through cellular signaling pathways of its receptors.

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, HFs undergo apoptosis and there is a decline in an apoptotic protein, Bcl-2, and an increase in a pro-apoptotic protein, Bax8. In several reports, IGF-I and IGF-II have prevented the follicle from developing catagen-like status9.

In many experimental reports, pro-inflammatory cytokines, such as IL-1α,β, TNF-α, and INF-γ, have been reported to induce apoptosis of hair bulb keratinocytes1012.

Platelet-derived growth factor (PDGF) is a potent mitogen produced in a variety of cell types including keratinocytes and endothelial cells, and is important for cell growth. Expression of PDGF isoforms in HFs in vitro can be influenced by treatment with cytokines that are known to be positive and negative regulators of HF growth activity13. Recently, PDGF also induced and maintained anagen phase in mouse hair cycling14. The effects of PDGF on HFs, that is induction and maintenance of anagen, is very similar to the effect of IGF-I on hair growth.

In the current study, expression of hair growth factors & cytokines (PDGF-A, PDGF-B, transforming growth factor [TGF]-β, interleukin [IL]-1α, IL-1β, tumor necrosis factor [TNF]-α, interferon [INF]-γ) and apoptosis-related molecules (Bax, Bcl-2, c-myc) were determined by reverse transcription polymerase chain reaction (RT-PCR), after treatment of cells with IGF-I using an organ culture model of human HFs. This experiment was done in order to examine the molecular mechanism underlying the effect of IGF-I on HFs.

Specimens
Human occipital scalp skin specimens were obtained from hair transplantation surgery, after informed consent. The medical ethical committee of the Yonsei University Wonju College of Medicine, Wonju, Korea, approved all described studies. The study was conducted according to the Declaration of Helsinki principles. Skin samples, used for HF microdissection and organ culture, were collected and stored in a refrigerator at 4℃.

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