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

维生素 D 和钙信号在表皮干细胞维持、激活和功能中的作用

• 批准号: 10265328
• 负责人: DANIEL David BIKLE
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265328
• 关键词: AXIN2 protein; Affect; Agonist; Binding; Blood Vessels; CD44 gene; Calcitriol; Calcium; Calcium Signaling; Calcium-Sensing Receptors; Cell Maintenance; Cell membrane; Cells; Clinical; Clinical Trials; Complex; Cytoskeleton; Data; Desmosomes; Diabetes Mellitus; Diglycerides; Disease; E-Cadherin; Endoplasmic Reticulum; Epidermis; Epithelial; Epithelial Attachment; Event; Failure; Funding; Future; Hair follicle structure; Inositol; Maintenance; Malnutrition; Mediating; Medical Care Costs; Membrane; Methods; Modeling; Movement; Mus; Natural regeneration; Phosphatidylinositol 4,5-Diphosphate; Phospholipase C; Phosphorylation; Play; Process; Proliferating; Protein Kinase C; Regulation; Role; STIM1 gene; Signal Transduction; Skin; Testing; Topical application; Veterans; Vitamin D; Vitamin D3 Receptor; base; cell motility; cell type; chronic wound; cost estimate; epidermal stem cell; epithelial wound; improved; inorganic phosphate; insight; keratinocyte; keratinocyte differentiation; migration; military veteran; receptor; response; sensor; stem cell biomarkers; stem cell function; stem cell migration; stem cell niche; stem cell population; stem cell proliferation; stem cells; wound; wound closure; wound healing

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 epidermis and hair follicle. 3. Determine the regulation of intracellular calcium signaling by VDR and CaSR and the role of such signaling in the activation and migration of stem cells after wounding. Poor wound healing is an important problem in the Veteran population. We expect our results will provide insight into the regulation of wound healing, potentially resulting in improved methods for treating chronic wounds by accelerating their re-epithelialization.

伤口愈合对生存至关重要。这是一个涉及许多不同细胞类型的多步骤过程。的 与该项目特别相关的是，创伤激活了毛囊间表皮（IFE）中的干细胞， 毛囊（HF）增殖并将其后代送到伤口再上皮化， 使表皮再生无法闭合伤口导致美国估计超过25美元的医疗费用 10亿人，影响650万人。我们之前的研究表明维生素D和钙信号 在这些事件中扮演重要角色。正如我们在初步数据中显示的那样，维生素D受体（VDR）和 钙敏感受体（CaSR）是维持和激活HF中干细胞所必需的 和IFE。在上一个融资周期中，我们发现缺乏VDR和CaSR与延迟有关 在伤口愈合方面。我们假设VDR和CaSR都是维持干细胞所必需的。 小生境及其在受伤后的激活。这种激活刺激它们的增殖和迁移以重新 使伤口上皮化。我们的初步数据支持这一假设，即缺失VDR（VDRKO）结果 在HF和IFE中干细胞龛中细胞数量的减少中， 损伤后上皮前缘细胞，以axin 2和CD 44的表达为标志物， 干细胞活化的减少，并且伤口处上皮的前缘被破坏， 减少上皮连接（E-钙粘蛋白/连环蛋白复合物），这似乎是迁移所需的， 角质细胞穿过伤口作为恢复表皮的第一步。此外，我们证明， 局部应用拟钙剂以激活CaSR或骨化三醇以激活VDR 愈合，增加干细胞的数量和增殖。在这些有希望的初步基础上， 现在提出确定钙和维生素D信号传导调节 干细胞对伤口的作用以及其后代随后使伤口再上皮化的能力作为第一步 修复表皮的能力我们计划检验的假设是：“角质形成细胞中的VDR和CaSR是 维持表皮干细胞生态位所需。此外，通过调节细胞内钙 依赖的信号传导机制，它们使表皮干细胞的活化、增殖和迁移成为可能。 细胞和它们的后代在创伤后使创伤再上皮化并随后再生 表皮”。为了验证这一假设，我们提出了以下三个目标。1确定维生素D和 通过其受体的钙信号传导在表皮干细胞功能中发挥独特和/或互补的作用 在上皮再生过程中。2.确定VDR和CaSR是否对股骨柄的维护至关重要 表皮和毛囊内的细胞龛。3.测定细胞内钙信号的调节， VDR和CaSR以及这种信号传导在创伤后干细胞活化和迁移中的作用。 伤口愈合不良是退伍军人群体的一个重要问题。我们希望我们的结果能提供 深入了解伤口愈合的调节，可能导致治疗慢性 加速伤口的上皮再生。

项目成果

Mediator 1 ablation induces enamel-to-hair lineage conversion in mice through enhancer dynamics.

• DOI: 10.1038/s42003-023-05105-5
• 发表时间: 2023-07-21
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Thaler, Roman;Yoshizaki, Keigo;Nguyen, Thai;Fukumoto, Satoshi;Den Besten, Pamela;Bikle, Daniel D.;Oda, Yuko
• 通讯作者: Oda, Yuko

Vitamin D Metabolism Revised: Fall of Dogmas.

• DOI: 10.1002/jbmr.3884
• 发表时间: 2019-11
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Bouillon, Roger;Bikle, Dan
• 通讯作者: Bikle, Dan

Role of vitamin D and calcium signaling in epidermal wound healing.

• DOI: 10.1007/s40618-022-01893-5
• 发表时间: 2023-02
• 期刊: JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
• 影响因子: 5.4
• 作者: Bikle, D. D.

Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review.

• DOI: 10.1016/j.bonr.2018.02.004
• 发表时间: 2018-06
• 期刊: Bone reports
• 影响因子: 2.5
• 作者: Bikle DD;Patzek S;Wang Y
• 通讯作者: Wang Y

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions.

• DOI: 10.1210/er.2018-00126
• 发表时间: 2019-08-01
• 期刊: Endocrine reviews
• 影响因子: 20.3
• 作者: Bouillon R;Marcocci C;Carmeliet G;Bikle D;White JH;Dawson-Hughes B;Lips P;Munns CF;Lazaretti-Castro M;Giustina A;Bilezikian J
• 通讯作者: Bilezikian J