Vitamin a metabolism in hair cycle regulation - 7. Project summary/abstract: studying the hair cycle provides an in vivo model for studying stem cell regulation that can be easily accessed,…

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Texas Woman's University $475,063 on August 1, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846).

The award funds research into vitamin A metabolism and its regulation of the hair follicle stem cell cycle, with specific focus on sex-dependent mechanisms. The research examines how sex hormones and exogenous retinoids alter endogenous retinoic acid synthesis within the hair follicle stem cell niche to maintain stem cell quiescence and prevent hair aging and loss. Work includes identifying vitamin A metabolism and signaling cross-talk between sex hormones and retinoic acid pathways, evaluating how these interactions affect hair follicle stem cells during aging, and investigating the dual role of retinoids in preventing cutaneous squamous cell carcinoma while addressing sex differences in hair loss and aging.

Performance occurs in Denton, Texas through July 31, 2029. The research uses the hair cycle as an in vivo model for stem cell regulation, with objectives addressing the central hypothesis that sex hormones regulate retinoic acid synthesis to maintain hair follicle stem cell quiescence and prevent hair aging. This is a Project Grant assistance award.

Vitamin a metabolism in hair cycle regulation - 7. Project summary/abstract: studying the hair cycle provides an in vivo model for studying stem cell regulation that can be easily accessed, manipulated, and visualized. Loss of hair follicle stem cells (hfscs) leads to hair aging and hair loss, while aberrant regulation of these hfscs contributes to cutaneous squamous cell carcinoma (cscc). Cscc is costly to treat and leads to metastasis and death. Hair loss leads to significant stigmatization, low self-esteem, anxiety, and reduced quality of life, which are worse in women. Hfsc quiescence is essential for their self- renewal. Hfsc quiescence is greater in females than males. Estrogen regulates hfsc quiescence in a SEX dependent manner. However, we do not understand the complete mechanisms for these SEX differences. Retinoids are a family of vitamin a derived compounds, which includes vitamin a (retinol) and its active metabolite retinoic acid (RA). RA regulated hfsc quiescence dose-dependently in vitro. Importantly, our data shows that dietary vitamin a and loss of RA synthesis also regulates hfscs in vivo. Retinoids prevented or worsened the development of cscc and hair loss in humans and mouse models, but few of these studies examined an effect of SEX. We and others found that SEX hormones regulated expression of RA synthesis and signaling genes and RA responses in a SEX dependent manner. RA, in turn, affects SEX hormone synthesis and signaling, suggesting the existence of an interaction between SEX hormones and RA signaling. The objectives in this application are to identify how SEX hormones and exogenous retinoids alter endogenous RA synthesis within the hfsc niche to maintain hfsc quiescence and determine how this affects hfscs and hair loss during aging. Our central hypothesis is that SEX hormones regulate RA synthesis to maintain hfsc quiescence to prevent hair aging. The specific aims are to: 1) identify the vitamin a metabolism and signaling cross talk with SEX hormone signaling to maintain quiescent hfscs in a SEX dependent manner; and 2) identify the role of SDR16C5 and SDR16C6 in hair aging in a SEX dependent manner. The approach is to treat whole body SDR16C5-/-/SDR16C6-/- double knockout mice with SEX hormone receptor agonists and antagonists and examine hfsc quiescence. We will also rescue these transgenic mice with synthetic retinoids. In addition, we will analyze hair cycling as these mice age. Understanding how SEX hormones and vitamin a metabolism interact in a SEX-dependent manner to regulate hair follicle stem cells in vivo is significant because IT will lead to the development of alternative SEX specific retinoid treatments with more specificity and fewer side effects than current retinoid therapies. Once we identify which vitamin a metabolism enzymes and rars are involved, we can target therapies to regulate endogenous RA synthesis and/or specific rars. The proposed research is innovative because IT will identify how endogenous RA synthesis is regulated in a SEX dependent manner using state of the art retinoid analysis technology.