Calcium and Vitamin D Signaling in the Epidermal Response to Wounding

Abstract

Wound healing is essential for survival. This is a multistep process involving a number of different cell types. In the skin wounding triggers an acute inflammatory response, with the innate immune system contributing both to protection against invasive organisms and to triggering the invasion of inflammatory cells into the wounded area. These cells release a variety of cytokines and growth factors that stimulate the proliferation and migration of dermal and epidermal cells to close the wound. In particular, wounding activates stem cells in the interfollicular epidermis (IFE) and hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound. 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. Vitamin D and calcium signaling are necessary for a normal innate immune and inflammatory response to wounding in the epidermis. Moreover, VDR is required for maintenance of hair follicle (HF) stem cells known to contribute to wound closure of the IFE. Mice lacking the calcium sensing receptor (CaSR) or the VDR when placed on a low calcium diet have delayed wound healing. This is associated with a reduction in the number of cells in the stem cell niches in both HF and IFE and reduced proliferation and migration in the cells at the leading edge of the epithelium after wounding. We hypothesize that at least part of this delay in wound closure is due to a reduction of stem cell activation and number in cells lacking the VDR and/or their failure of activation by calcium in cells lacking the CaSR, and are currently investigating this concept. Keywords: Calcium, epidermis, ora 1, signaling, stim1, vitamin D, wounding.