# Vitamin D and Calcium signaling in epidermal stem cell maintenance, activation, and function

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

Wound healing is essential for survival. This is a multistep process involving a number of different cell types. Of
particular relevance to this project is that wounding activates stem cells in the interfollicular epidermis (IFE) and
hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound and subsequently
regenerate the epidermis. Failure to close wounds leads to medical costs estimated in the US at over $25
billion and affecting 6.5 million people. Our previous studies have shown that vitamin D and calcium signaling
play important roles in these events. As we show in preliminary data, both the vitamin D receptor (VDR) and
calcium sensing receptor (CaSR) are required for the maintenance and activation of the stem cells in the HF
and IFE. In the previous funding cycle we showed that lack of the VDR and CaSR are associated with a delay
in wound closure. We hypothesized that VDR and CaSR are required both for the maintenance of the stem cell
niches and their activation following wounding. This activation stimulates their proliferation and migration to re-
epithelialize the wound. Our preliminary data support this hypothesis in that deletion of VDR (VDRKO) results
in a reduction in the number of cells in the stem cell niches in both HF and IFE, that proliferation is reduced in
the cells at the leading edge of the epithelium after wounding, that expression of axin 2 and CD44 as markers
of stem cell activation is reduced, and that the leading edge of the epithelium at the wound is disorganized with
reduction in the epithelial junctions (E-cadherin/catenin complexes) that appear to be required for migration of
the keratinocytes across the wound as a first step in restoring the epidermis. Moreover, we demonstrated that
topical application of a calcimimetic to activate the CaSR or calcitriol to activate the VDR accelerates wound
healing, increasing the number and proliferation of the stem cells. Building on these promising preliminary we
now propose to determine the mechanisms by which calcium and vitamin D signaling regulate the response of
stem cells to wounding and the subsequent ability of their progeny to re-epithelialize the wound as the first step
in restoring the epidermis. The hypothesis that we plan to test is: “The VDR and CaSR in keratinocytes are
required for the maintenance of the epidermal stem cell niche. Moreover, by regulating intracellular calcium
dependent signaling mechanisms they enable the activation, proliferation, and migration of epidermal stem
cells and their progeny following wounding to re-epithelialize the wound and subsequently regenerate the
epidermis”. To test this hypothesis we propose the following three aims. 1 Determine whether vitamin D and
calcium signaling via their receptors play distinct and/or complementary roles in epidermal stem cell function
during re-epithelialization. 2. Determine whether VDR and CaSR are essential for the maintenance of the stem
cell niches within the epiderm...

## Key facts

- **NIH application ID:** 9859322
- **Project number:** 5I01BX003814-03
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** DANIEL David BIKLE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859322

## Citation

> US National Institutes of Health, RePORTER application 9859322, Vitamin D and Calcium signaling in epidermal stem cell maintenance, activation, and function (5I01BX003814-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9859322. Licensed CC0.

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