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.

伤口愈合对于生存至关重要。这是一个涉及多种不同细胞类型的多步过程。的 与该项目特别相关的是，绘制激活流体表皮中的干细胞（IFE）和 毛囊（HF）扩散并发送其后代以重新上皮化伤口，然后 再生表皮。未能关闭伤口会导致美国估计的医疗费用超过25美元 十亿，影响650万人。我们以前的研究表明，维生素D和钙信号传导 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接收器（VDR）和 钙传感受体（CASR）是HF中干细胞维持和激活所必需的 和ife。在上一个资金周期中，我们表明缺乏VDR和CASR与延迟有关 在伤口闭合。我们假设VDR和CASR都需要维护干细胞 利基及其胜利后的激活。这种激活刺激了它们的增殖和迁移至 上皮化伤口。我们的初步数据支持了这一假设，因为删除了VDR（VDRKO）结果 在HF和IFE中干细胞壁细胞壁细胞中的细胞数量减少时，这种增殖均减少 绘制后上皮前缘的细胞，Axin 2和CD44的表达为标记 干细胞激活的激活减少，伤口处上皮的前缘与 迁移似乎需要的上皮连接（E-钙粘蛋白/catenin络合物）的降低 在伤口上的角质形成细胞是恢复表皮的第一步。而且，我们证明了 钙化的局部应用激活CASR或骨化三醇以激活VDR加速伤口 愈合，增加干细胞的数量和增殖。以这些有希望的初步为基础 现在建议确定钙和维生素D信号调节的机制 干细胞赢得并随后其后代重新上皮化伤口的能力为第一步 在恢复表皮。我们计划测试的假设是：“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，通过控制细胞内钙 依赖的信号传导机制它们可以激活，增殖和迁移表皮茎 细胞和他们的后代在获胜后重新上皮化获胜，然后再生 表皮”。为了检验这一假设，我们提出了以下三个目标。1确定维生素D和是否是否 通过其接收器的钙信号传导在表皮干细胞功能中起独特的和/或互补作用 在重新上皮化期间。 2。确定VDR和CASR是否对于维持茎 表皮和毛囊中的细胞壁细分。 3。确定细胞内钙信号传导的调节 VDR和CASR以及这种信号在生活后的干细胞激活和迁移中的作用。 在退伍军人人群中，伤口愈合不佳是一个重要的问题。我们预计我们的结果将提供 深入了解伤口愈合的调节，可能导致改进的治疗方法 通过加速其再上皮化来伤口。

项目成果

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

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