Dietary Vitamin A Impacts Refractory Telogen.

Liye Suo,Helen B. Everts,John P. Sundberg,Natalia Y. Kedishvili,Christine VanBuren,Eylul Damla Hovland

doi:10.3389/fcell.2021.571474

Abstract

Hair follicles cycle through periods of growth (anagen), regression (catagen), rest (telogen), and release (exogen). Telogen is further divided into refractory and competent telogen based on expression of bone morphogenetic protein 4 (BMP4) and wingless-related MMTV integration site 7A (WNT7A). During refractory telogen hair follicle stem cells (HFSC) are inhibited. Retinoic acid synthesis proteins localized to the hair follicle and this localization pattern changed throughout the hair cycle. In addition, excess retinyl esters arrested hair follicles in telogen. The purpose of this study was to further define these hair cycle changes. BMP4 and WNT7A expression was also used to distinguish refractory from competent telogen in C57BL/6J mice fed different levels of retinyl esters from two previous studies. These two studies produced opposite results; and differed in the amount of retinyl esters the dams consumed and the age of the mice when the different diet began. There were a greater percentage of hair follicles in refractory telogen both when mice were bred on an unpurified diet containing copious levels of retinyl esters (study 1) and consumed excess levels of retinyl esters starting at 12 weeks of age, as well as when mice were bred on a purified diet containing adequate levels of retinyl esters (study 2) and remained on this diet at 6 weeks of age. WNT7A expression was consistent with these results. Next, the localization of vitamin A metabolism proteins in the two stages of telogen was examined. Keratin 6 (KRT6) and cellular retinoic acid binding protein 2 (CRABP2) localized almost exclusively to refractory telogen hair follicles in study 1. However, KRT6 and CRABP2 localized to both competent and refractory telogen hair follicles in mice fed adequate and high levels of retinyl esters in study 2. In mice bred and fed an unpurified diet retinol dehydrogenase SDR16C5, retinal dehydrogenase 2 (ALDH1A2), and cytochrome p450 26B1 (CYP26B1), enzymes and proteins involved in RA metabolism, localized to BMP4 positive refractory telogen hair follicles. This suggests that vitamin A may contribute to the inhibition of HFSC during refractory telogen in a dose dependent manner.

Highlights

The hair follicle has a self-cycling ability
We ran Co-IHC with the Vector Labs bone morphogenetic protein 4 (BMP4) antibody, keratin 6 (KRT6) and cellular retinoic acid binding protein 2 (CRABP2) on samples from all of the diets in the retinyl ester feeding studies. We found that both KRT6 and CRABP2 localized to the inner bulge only when BMP4 was in the dermis in all but one mouse in study 1 (Figures 4A–D,I–L arrow and arrowhead and Supplementary Figure 6)
In mice bred on an unpurified diet, excess levels of retinyl esters lead to a greater percentage of hair follicles in refractory telogen

Summary

Introduction

The hair follicle has a self-cycling ability. It goes through a regeneration phase (anagen), a degenerative phase (catagen) involving the apoptosis and loss of the lower two-thirds of the hair follicle, a resting phase (telogen), and a release phase (exogen) (Chase et al, 1951; Milner et al, 2002). WNT7A and WNT7B are directly inhibited by BMP signaling and relief of this inhibition is important for the initiation of the new hair cycle (Kandyba et al, 2013; Kandyba and Kobielak, 2014) According to this theory, anagen initiation can only occur if the hair follicle is in competent telogen. BMP6 and FGF18 are secreted from inner bulge cells, which are marked by keratin 6 (KRT6) (Hsu et al, 2011) This KRT6 layer has been called suprabasal bulge cells (Wang et al, 2016), companion layer of the club hair, and trichilemmal keratin (Higgins et al, 2009). These inner bulge KRT6 positive cells anchor the hair follicle to the club hair and are involved in shedding hair during late exogen (Higgins et al, 2009, 2011)

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