Coordinated Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells

真皮乳头细胞对毛发生长和色素沉着的协调调节

• 批准号: 8518166
• 负责人: Yuhang Zhang
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518166
• 关键词: Ablation; Autocrine Communication; Biological Assay; Biological Models; Cell Communication; Cell Nucleus; Cells; Data Reporting; Dermal; Development; Disease; Engineering; Epidermis; Epithelial; Etiology; Fibroblasts; Goals; Growth; Growth Disorders; Hair; Hair Cells; Hair follicle structure; Knowledge; Knowledge acquisition; Maintenance; Mediating; Membrane Proteins; Mesenchymal; Mission; Molecular; Mus; Natural regeneration; Nature; Organ; Pathway interactions; Pigmentation physiologic function; Pigments; Population; Prevention approach; Protein Binding; Proteins; Public Health; Regulation; Reporter; Research; Role; Signal Transduction; Signaling Molecule; Skin; Sorting - Cell Movement; Staging; Stem cells; Structure; Testing; Tissue Engineering; Transplantation; Wnt proteins; Work; base; design; in vivo; innovation; interest; melanocyte; mouse model; novel; novel strategies; postnatal; self-renewal; skin disorder; stem; stem cell biology; tissue regeneration; tongue papilla; treatment strategy

DESCRIPTION (provided by applicant): There is a fundamental knowledge gap in understanding how dermal papilla cells (DPCs) instruct the heterogeneous follicular stem cells (SCs) to react in a synchronized manner for a healthy hair growth. The hair follicle is a self-renewing mini-organ supported by the proliferation and differentiation of follicular SCs of different lineages, including epithelial stem cells (EpSCs) and melanocyte stem cells (MSCs). Continued existence of this gap limits our ability to design the effective strategies for the treatment of hair growth disorder, and for the regeneration of hair follicles in cases of congenita hair loss or skin wounds. The long-term goal of my research is to discover the molecular pathways in DPCs that could be manipulated for hair regeneration and pigmentation. The overall objective in this application is to characterize the Wnt/¿-catenin signaling loop by which DPCs interact with and guide follicular SCs and their progeny to promote hair growth. Wnt/¿-catenin signaling activity is indispensable for the coordinated activation of EpSCs and MSCs at anagen onset. Wnt proteins can also prolong the ability of isolated DPCs to induce hair. However the origin and nature of the endogenous Wnt signals to initiate these activities remain unidentified. Our central hypothesis is that specific Wnt proteins are first generated in DPCs at anagen onset as an autocrine signal, and subsequently function in a reciprocal signaling loop to orchestrate the activation of follicular SCs to rebuild pigmented hair. The rationale is that the successful completion of the proposed research will provide detailed characterization of the nature of Wnt proteins from DPCs and the mechanism by which the Wnt/¿-catenin signaling in DPCs guide follicular SCs and their progeny through the normal cyclic growth of hair follicles. This hypothesis will be tested by pursuing three specific aims: 1) identify the DPC populations that respond to Wnt/¿-catenin signals during the postnatal hair cycle; 2) determine whether Wnt proteins from DPCs are required to activate Wnt/¿-catenin signaling in the postnatal hair cycle and to induce and sustain hair growth and pigmentation; and 3) determine whether the activation of Wnt/¿-catenin signaling in DPCs is sufficient to regulate the initiation and maintenance of postnatal hair growth and pigmentation. Our proposed research is innovative because we are the first to engineer an in vivo mouse model system to probe the nature of Wnt proteins from DPCs and their role as an activating signal to prime DPCs for hair induction and activate follicular EpSCs and MSCs in a synchronized manner. The contribution from this proposed research is significant because it will deepen our understanding of the role of DPCs as a signaling center in the regulation of pigmented hair growth and may ultimately permit the development of novel strategies for regenerating hair follicles in cases of severe skin wounds and for the treatment of hair growth disorders. Ultimately, the knowledge obtained from our research will also contribute to a broader and deeper understanding of stem cell biology and tissue engineering.

描述（由申请人提供）：在理解毛乳头细胞（DPC）如何指导异质毛囊干细胞（SC）以同步方式反应以促进健康毛发生长方面存在基本知识差距。毛囊是一个自我更新的微型器官，由不同谱系的毛囊干细胞（包括上皮干细胞（EpSC）和黑素细胞干细胞（MSC））的增殖和分化支持。这种差距的持续存在限制了我们设计治疗毛发生长障碍的有效策略的能力，以及在先天性脱发或皮肤创伤的情况下毛囊再生的能力。我研究的长期目标是发现DPC中的分子通路，这些分子通路可以被操纵用于毛发再生和色素沉着。本申请的总体目标是表征Wnt/β-连环蛋白信号传导环，DPC通过该信号传导环与毛囊SC及其后代相互作用并引导毛囊SC及其后代促进毛发生长。Wnt/β-连环蛋白信号传导活性对于生长期开始时EpSC和MSC的协调激活是不可或缺的。Wnt蛋白还可以延长分离的DPC诱导毛发的能力。然而，启动这些活动的内源性Wnt信号的起源和性质仍然没有确定。我们的中心假设是，特定的Wnt蛋白首先在生长期开始时作为自分泌信号在DPC中产生，随后在相互信号传导回路中起作用，以协调毛囊SC的激活以重建着色的毛发。基本原理是，拟议研究的成功完成将提供来自DPC的Wnt蛋白质的性质的详细表征，以及DPC中的Wnt/<$-连环蛋白信号传导引导毛囊SC及其后代通过毛囊的正常周期生长的机制。这一假设将通过追求三个具体目标来检验：1）鉴定在出生后毛发周期中响应Wnt/<$-连环蛋白信号的DPC群体; 2）确定来自DPC的Wnt蛋白是否是在出生后毛发周期中激活Wnt/<$-连环蛋白信号并诱导和维持毛发生长和色素沉着所必需的;以及3）确定Wnt/<$-连环蛋白信号的激活是否是在出生后毛发周期中诱导和维持毛发生长和色素沉着所必需的。DPC中的β-catenin信号足以调节出生后毛发生长和色素沉着的起始和维持。我们提出的研究是创新的，因为我们是第一个设计体内小鼠模型系统来探测来自DPC的Wnt蛋白的性质及其作为激活信号的作用，以引发DPC用于毛发诱导并以同步方式激活毛囊EpSC和MSC。这项拟议研究的贡献是重要的，因为它将加深我们对DPC作为色素头发生长调节信号中心的作用的理解，并可能最终允许开发在严重皮肤伤口和治疗头发生长障碍的情况下再生毛囊的新策略。最终，从我们的研究中获得的知识也将有助于更广泛和更深入地了解干细胞生物学和组织工程。