Suppression of FGF5 and FGF18 Expression by Cholesterol-Modified siRNAs Promotes Hair Growth in Mice

Abstract

FGF5 and FGF18 are key factors in the regulation of the hair follicle cycle. FGF5 is overexpressed during the late anagen phase and serves as a crucial regulatory factor that promotes the anagen-to-catagen transition in the hair follicle cycle. FGF18, which is overexpressed during the telogen phase, mainly regulates the hair follicle cycle by maintaining the telogen phase and inhibiting the entry of hair follicles into the anagen phase. The inhibition of FGF5 may prolong the anagen phase, whereas the inhibition of FGF18 may promote the transition of the hair follicles from the telogen phase to the anagen phase. In the present study, we used siRNA to suppress FGF5 or FGF18 expression as a way to inhibit the activity of these genes. Using qPCR, we showed that FGF5-targeting siRNA modified by cholesterol was more effective than the same siRNA bound to a cell-penetrating peptide at suppressing the expression of FGF5 both in vitro and in vivo. We then investigated the effects of the cholesterol-modified siRNA targeting either FGF5 or FGF18 on the hair follicle cycle in a depilated area of the skin on the back of mice. The cholesterol-modified siRNA, delivered by intradermal injection, effectively regulated the hair follicle cycle by inhibiting the expression of FGF5 and FGF18. More specifically, intradermal injection of a cholesterol-modified FGF5-targeted siRNA effectively prolonged the anagen phase of the hair follicles, whereas intradermal injection of the cholesterol-modified FGF18-targeted siRNA led to the mobilization of telogen follicles to enter the anagen phase earlier. The inhibitory effect of the cholesterol-modified FGF18-targeted siRNA on FGF18 expression was also evaluated for a topically applied siRNA. Topical application of a cream containing the cholesterol-modified FGF18-targeted siRNA on a depilated area of the skin of the back of mice revealed comparable inhibition of FGF18 expression with that observed for the same siRNA delivered by intradermal injection. These findings suggested that alopecia could be prevented and hair regrowth could be restored either through the intradermal injection of cholesterol-modified siRNA targeting FGF5 or FGF18 or the topical application of FGF18 siRNA.

Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy

“…Nevertheless, certain issues hamper this approach to be developed [ 141 ]. Cholesterol-modified siRNA has also been evidenced to be worthy for topical application for alopecia treatment [ 142 ]. Interestingly, the exosomes—membrane-bound extracellular vesicles that are functionally pleiotropic nanoparticles—have also demonstrated their positive role on hair growth in cultured HF [ 77 , 140 , 143 ].…”

Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response

“…It has been suggested that FGF18 is a pleiotropic growth factor that can stimulate proliferation in several different tissues. 95 The decrease in FGF18 that reached a nadir at 2 h post-hypoglycaemia, hypothetically may suggest a protective role in reducing growth stimulation in the face of a low blood glucose; however, no role for FGF18 has been identified in T2D. There were no changes seen for FGF8 that has been suggested to protect against oxidative stress in prolonged hypoglycaemia.…”

“…These novel data showed that FGF18 was significantly decreased at 2 h in both T2D and controls with no difference between the cohorts. It has been suggested that FGF18 is a pleiotropic growth factor that can stimulate proliferation in several different tissues 95 . The decrease in FGF18 that reached a nadir at 2 h post‐hypoglycaemia, hypothetically may suggest a protective role in reducing growth stimulation in the face of a low blood glucose; however, no role for FGF18 has been identified in T2D.…”

Methionine can subside hair follicle development prejudice of heat‐stressed rex rabbits

“…There are three phases in the hair growth cycle that is regulated by many factors, including Wnt‐β‐catenin signal, transforming growth factor β (TGFβ)/Noggin‐bone morphogenetic protein (BMP) signal, epithelial growth factor (EGF), insulin‐like growth factor 1 (IGF1), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), sonic hedgehog (Shh) and Notch. Wnt, Notch, HGF, FGF, IGF‐1, EGF, Shh, and Noggin positively regulate hair follicle development 10–16 . BMPs can inhibit hair follicle development 17 …”

“…Wnt, Notch, HGF, FGF, IGF-1, EGF, Shh, and Noggin positively regulate hair follicle development. [10][11][12][13][14][15][16] BMPs can inhibit hair follicle development. 17 Methionine is an essential amino acid containing sulfur, especially important for fur animals.…”