Inductive properties of the dermal papilla of the hair follicle

毛囊真皮乳头的感应特性

• 批准号: 8373369
• 负责人: BRUCE A MORGAN
• 金额: $ 38.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-05 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373369
• 关键词: Ablation; Address; Adult; Behavior; Biological Models; Cell Count; Cell Death; Cell Size; Cells; Cellularity; Characteristics; Collaborations; Dermal; Emotional; Epithelial; Epithelial Cells; Epithelium; Frequencies; Gene Expression; Genes; Graafian Follicles; Growth; Hair; Hair Part; Hair bulb structure; Hair follicle structure; Hair shaft structure; In Vitro; Individual; Maintenance; Mediating; Mesenchymal; Mesenchyme; Methods; Molds; Morphogenesis; Morphology; Mouse Strains; Mus; Natural regeneration; Organ; Organ Size; Organism; Organogenesis; Pattern Formation; Phenotype; Platelet-Derived Growth Factor; Population; Prevention; Probability; Process; Production; Property; Recruitment Activity; Regenerative Medicine; Regulation; Research; Role; Shapes; Signal Pathway; Signal Transduction; Skin; Specific qualifier value; Stem cells; Structure; System; Testing; Time; To specify; Transgenic Organisms; Wild Type Mouse; Work; adult stem cell; cell type; critical period; gain of function; gain of function mutation; in vivo; insight; keratinocyte; progenitor; psychologic; research study; restoration; stem cell biology; stem cell population; tongue papilla; tool; transcription factor

DESCRIPTION (provided by applicant): The hair follicle has emerged as an important focus of research not only because of the psychological and emotional impacts of hair loss or excessive hair growth, but also because the hair follicle is periodically regenerated from a resident stem cell population in the adult and this serves an important model system in stem cell biology, regenerative medicine, and organogenesis. The hair follicle is composed of two principle components, (1)an epithelial population that comprises the majority of the follicle and gives rise to the differentiated cells that form the hair shaft and its surrounding cell layers in the follicl, and (2) a specialized mesenchymal population, the dermal papilla, that guides the activities of these epithelial cells. We have developed methods to manipulate gene expression specifically in the dermal papilla of the hair follicles after they have formed and exploited these to study the signaling between the dermal papilla and the follicular epithelium. This has provided insight onto signals that impinge on DP cells to control the production of signals that in turn regulate keratinocyte behavior and hair growth. These experiments suggest a second mechanism dictating the size and shape of the hair produced that occurs through active and dynamic regulation of the number of DP cells per follicle. The size of the hair correlates with the number of DP cells /follicle. One aim of this research is to test the significance of this correlation by selectively ablating DP cells in adult hair follicles and evaluating both the effects on hair growt and cycling as well as mechanisms that may compensate for cell death in the DP compartment. A second is to characterize the role of a transcription factor, Sox2 that is expressed in the DP. The phenotypes we observe after deleting the Sox2 gene specifically in the DP suggests it acts to regulate DP size during a critical period in follicular regeneration. We will test this hypothess with gain of function and rescue experiments and identify the gene expression changes that mediate Sox2 function in the DP. Signals within and between follicles, as well as from surrounding cell types in the skin all contribute to specifying DP size. To characterize those signals, we will extend our studies using DP specific blockade of additional signaling pathways to characterize how they contribute to these two mechanisms, signal production per DP cell and regulation of DP cell number. Successful completion of this work will provide insight into the mechanisms by which a progenitor pool interacts with and molds its niche and how that niche contributes to the regulation organ size and shape in the context of the changing needs of the organism. PUBLIC HEALTH RELEVANCE: The hair follicle is formed from adult stem cells under the influence of a second cell population, the dermal papilla, that directs these cells to form a hair f specific size and shape. By manipulating gene activity in the dermal papilla, we will identify the mechanisms by which the size of cell progenitor pools and their supporting niche populations are generated in the hair follicle, and how that dictates the size and shape of the hair. This research will have implications for the prevention of hair loss or restoration of defective hair follicles, and will also shed insight into the more general mechanisms that regulate organ size and shape.

描述（由申请人提供）：毛囊已成为研究的重要焦点，不仅因为脱发或毛发过度生长对心理和情感的影响，还因为毛囊定期从常驻干细胞群中再生在成人中，这为干细胞生物学、再生医学和器官发生提供了重要的模型系统。毛囊由两个主要组成部分组成，(1) 上皮细胞群，构成毛囊的大部分，并产生形成毛干及其毛囊周围细胞层的分化细胞，以及 (2) 专门的毛囊细胞。间充质群体，即真皮乳头，引导这些上皮细胞的活动。我们开发了在毛囊真皮乳头形成后专门操纵基因表达的方法，并利用这些方法来研究真皮乳头和毛囊上皮之间的信号传导。这提供了对影响 DP 细胞的信号的深入了解，以控制信号的产生，进而调节角质形成细胞的行为和毛发生长。这些实验提出了第二种决定头发大小和形状的机制，这种机制是通过主动和动态调节每个毛囊的 DP 细胞数量而发生的。头发的大小与 DP 细胞/毛囊的数量相关。这项研究的一个目的是通过选择性消融成人毛囊中的 DP 细胞并评估对毛发生长和周期的影响以及可能补偿 DP 室中细胞死亡的机制来测试这种相关性的重要性。第二个是表征在 DP 中表达的转录因子 Sox2 的作用。我们在 DP 中特异删除 Sox2 基因后观察到的表型表明，它在卵泡再生的关键时期起到调节 DP 大小的作用。我们将通过功能获得和拯救实验来检验这一假设，并确定介导 DP 中 Sox2 功能的基因表达变化。毛囊内部和毛囊之间的信号以及来自皮肤周围细胞类型的信号都有助于确定 DP 大小。为了表征这些信号，我们将使用 DP 特异性阻断其他信号通路来扩展我们的研究，以表征它们如何对这两种机制（每个 DP 细胞的信号产生和 DP 细胞数量的调节）做出贡献。这项工作的成功完成将深入了解祖细胞库与其相互作用并塑造其生态位的机制，以及该生态位如何在生物体不断变化的需求背景下调节器官的大小和形状。 公共健康相关性：毛囊是在第二个细胞群（真皮乳头）的影响下由成体干细胞形成的，真皮乳头引导这些细胞形成特定大小和形状的头发。通过操纵真皮乳头中的基因活性，我们将确定毛囊中细胞祖细胞库的大小及其支持生态位群的产生机制，以及它如何决定头发的大小和形状。这项研究将对预防脱发或修复有缺陷的毛囊产生影响，还将深入了解调节器官大小和形状的更一般机制。