Vitamin D Receptor Is Required for Proliferation, Migration, and Differentiation of Epidermal Stem Cells and Progeny during Cutaneous Wound Repair

Epidermal stem cells residing in the skin play an essential role in epidermal regeneration. When skin is injured, the stem cells are first activated to proliferate, and subsequently the progeny migrate and differentiate to regenerate the epidermis. Here, we demonstrate that the vitamin D receptor (VDR) is essential for these processes to occur. The requirement for VDR on epidermal stem cell function was revealed in conditional VDR knockout mice, in which VDR was deleted from stem cells and progeny, and mice were maintained on a low calcium diet. First, self-renewal and niche formation of epidermal stem cells were impaired. Wound-induced activation of epidermal stem cells was blunted associated with a reduction of beta-catenin signaling. Second, wound induced migration of stem cells and progeny was impaired as shown by lineage tracing and delayed migration of VDR silenced cells. Epidermal differentiation of progeny was impaired at the wounding site associated with reduced E-cadherin expression. Deletion of VDR also changed stem cell fate blunting hair development, increasing sebaceous glands, and altering expression and location of epidermal markers. These results suggest that VDR is required for self-renewal, migration, and differentiation of epidermal stem cells and progeny during cutaneous wound healing.