Inductive properties of the dermal papilla of the hair follicle

描述（由申请人提供）：毛囊已经成为一个重要的研究焦点，不仅是因为脱发或头发过度生长对心理和情感的影响，而且还因为毛囊是由成人体内的常住干细胞群体周期性再生的，这是干细胞生物学、再生医学和器官发生的重要模型系统。毛囊由两个主要组成部分组成，(1)上皮细胞群，包括毛囊的大部分，并产生分化的细胞，形成毛囊中的毛干及其周围的细胞层；(2)专门的间充质细胞群，真皮乳头，指导这些上皮细胞的活动。我们已经开发了在毛囊形成后特异性操纵毛乳头基因表达的方法，并利用这些方法研究毛乳头和毛囊上皮之间的信号传导。这提供了对影响DP细胞以控制信号产生的信号的见解，这些信号反过来调节角质细胞的行为和头发生长。这些实验表明，通过对每个毛囊DP细胞数量的主动和动态调节，还有另一种机制决定了毛发的大小和形状。毛发的大小与DP细胞/毛囊的数量有关。本研究的目的之一是通过选择性地切除成人毛囊中的DP细胞来测试这种相关性的重要性，并评估对头发生长和循环的影响，以及可能补偿DP室中细胞死亡的机制。第二个是表征转录因子Sox2在DP中表达的作用。我们在卵泡再生的关键时期特异性地删除Sox2基因后观察到的表型表明，它在卵泡再生的关键时期调节卵泡再生的大小。我们将通过功能增益和救援实验来验证这一假设，并确定在DP中介导Sox2功能的基因表达变化。毛囊内部和之间的信号，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，以表征它们如何促进这两种机制，每个DP细胞的信号产生和DP细胞数量的调节。这项工作的成功完成将有助于深入了解祖池与其生态位相互作用和塑造的机制，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。

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.