Endogenous Retinoids in the Pathogenesis of Alopecia Areata

Duncan, F. Jason; Silva, Kathleen A.; Johnson, Claudia C.; King, Benjamin L.; Szatkiewicz, Jin P.; Kamdar, Sonya P.; Ong, David E.; Napoli, Joseph L.; Wang, Jinshan; King, Lloyd E.; Whiting, David; McElwee, Kevin J.; Sundberg, John P.; Everts, Helen B.

doi:10.1038/jid.2012.344

Cited by 54 publications

(64 citation statements)

References 88 publications

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“…We are using control samples from our previous vitamin A feeding study in C3H/HeJ mice. 18 We found that both nuclear localized CTNNB1 and WNT7A were dose dependently increased by dietary vitamin A. These findings extend the knowledge of vitamin A signaling in skin SCs.…”

Section: Introductionsupporting

confidence: 83%

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Dietary vitamin A regulates wingless-related MMTV integration site signaling to alter the hair cycle

Suo

Sundberg

Everts

2014

Exp Biol Med (Maywood)

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Alopecia areata is an autoimmune hair loss disease caused by a cell mediated immune attack of the lower portion of the cycling hair follicle. Feeding mice 3–7 times the recommended level of dietary vitamin A accelerated the progression of alopecia areata in the graft-induced C3H/HeJ mouse model of alopecia areata. In this study we also found that dietary vitamin A, in a dose dependent manner, activated the hair follicle stem cells to induce the development and growth phase of the hair cycle (anagen), which may have made the hair follicle more susceptible to autoimmune attack. Our purpose here is to determine the mechanism by which dietary vitamin A regulates the hair cycle. We found that vitamin A in a dose dependent manner increased nuclear localized beta-catenin (CTNNB1; a marker of canonical WNT signaling) and levels of WNT7A (wingless-related MMTV integration site 7A) within the hair follicle bulge in these C3H/HeJ mice. These findings suggest that feeding mice high levels of dietary vitamin A increases WNT signaling to activate hair follicle stem cells.

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Section: Introductionsupporting

confidence: 83%

“…18 Control mice had their own dorsal skin removed and rotated 180 degrees in a sham surgery. Recipient and control C3H/HeJ mice were fed an AIN93 Maintenance diet containing 0 (n=8), 4 (n=7), 12 (n=9), or 28 (n=8) IU vitamin A/g diet (Research Diets, Inc., New Brunswick, NJ) starting two weeks before these mice were grafted.…”

Section: Methodsmentioning

confidence: 99%

Dietary vitamin A regulates wingless-related MMTV integration site signaling to alter the hair cycle

Suo

Sundberg

Everts

2014

Exp Biol Med (Maywood)

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“…RNA samples from 3 AA graft and 3 normal graft-recipient mice were used at each time point and processed using the MOE430v2.0 GeneChip™ (Affymetrix) as described and reported previously (Duncan et al, 2013; McPhee et al, 2012). Briefly, skin and spleen samples were harvested in an RNAse free manner and stored in RNAlater (Ambion, Austin, TX) per the manufacturer’s instructions and homogenized in TRIzol (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Dermal lymphatic dilation in a mouse model of alopecia areata

Sundberg

Pratt

Silva

et al. 2016

Experimental and Molecular Pathology

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Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20 weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10 weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention.

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“…Endogenous retinoids play a key role in the pathogenesis of AA [96]. Genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased both in AA mice, and in biopsies from AA patients.…”

Section: Aa Alopecia Totalis and Alopecia Universalismentioning

confidence: 99%

Drug discovery for alopecia: gone today, hair tomorrow

Santos

Avci

Hamblin

2015

Expert Opinion on Drug Discovery

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Introduction Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. Areas covered In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8+NK group 2D-positive (NKG2D+) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. Expert opinion The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play.

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Endogenous Retinoids in the Pathogenesis of Alopecia Areata

Cited by 54 publications

References 88 publications

Dietary vitamin A regulates wingless-related MMTV integration site signaling to alter the hair cycle

Dietary vitamin A regulates wingless-related MMTV integration site signaling to alter the hair cycle

Dermal lymphatic dilation in a mouse model of alopecia areata

Drug discovery for alopecia: gone today, hair tomorrow

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