Urothelial Stem Cells

摘要 这个项目建立在首席调查员在研究尿路上皮方面的丰富经验的基础上 分化和角质形成干细胞，旨在提供对膀胱的更好的了解 尿路上皮干细胞。尽管尿路上皮干细胞在动态平衡中具有核心重要性， 膀胱的再生和肿瘤发生，其确切的位置和性质仍然是 不完全理解。有几个问题阻碍了这一领域的进展。例如, 由于“尿路上皮”一词被用来描述表达尿路蛋白的上皮细胞 整个尿路，包括肾盆、输尿管、膀胱和近端尿路，通常被认为是 所有这些部位的尿路都是一样的。此外，对膀胱尿路上皮干细胞的研究已经 仅限于膀胱本身，而对尿路上皮干细胞以外的研究尚未引起关注 膀胱本身。然而，我们最近发现输尿管膀胱交界处(UVJ) 拥有一大群强标记(标记保留)干细胞。一个主要星系团的存在 位于膀胱输尿管开口附近的膀胱本身外的干细胞，让人想起 干细胞位于角膜缘区域的角膜外的角膜上皮细胞，以及 毛囊隆起干细胞，虽然在表皮之外，但参与表皮修复。 该项目的目标是更好地了解UVJ干细胞的特性和体内功能 细胞及其与膀胱和输尿管尿路上皮干细胞的关系。这些研究可以 提高我们对尿路上皮动态平衡、再生和疾病的理解，包括 化生和尿路感染。为了实现这些目标，我们将追求三个具体目标： 将研究：(I)尿路上皮谱系和干细胞的分子标记，(Ii)尿路上皮细胞的生物学功能 尿路上皮干细胞，以及(Iii)Wnt通路在调节尿路上皮干细胞中的可能作用 细胞。

Summary This project builds upon the Principal Investigator’s extensive experience in studying urothelial differentiation and keratinocyte stem cells, and aims at providing a better understanding of bladder urothelial stem cells. Despite the central importance of urothelial stem cells in the homeostasis, regeneration and tumorigenesis of the bladder, their precise location and properties are still incompletely understood. There are several issues that hinder the progress in this field. For example, since the term “urothelium” is used to describe the uroplakin-expressing epithelium that covers the entire urinary tract including the renal pelvis, ureter, bladder and proximal urethra, it is often assumed that urothelia of all these sites are the same. In addition, studies on bladder urothelial stem cells have been limited to the bladder per se and no attention has been paid to urothelial stem cells outside of the bladder proper. However, we have recently discovered that ureterovesicular junction (UVJ) harbors a large cluster of strongly labeled (label-retaining) stem cells. The presence of a major cluster of stem cells outside of the bladder proper, located near the bladder-ureter orifice, is reminiscent of the corneal epithelium whose stem cells reside outside of the corneal proper in the limbal zone, and the follicular bulge stem cells that, although outside of the epidermis, are involved in epidermal repair. The goals of this project are to better understand the properties and in vivo functions of the UVJ stem cells, and their relationships with the bladder and ureteral urothelial stem cells. These studies can improve our understanding of urothelial homeostasis, regeneration, and diseases including metaplasia and urinary tract infection. To reach these goals, we will pursue three Specific Aims that will study: (i) molecular markers of urothelial lineages and stem cells, (ii) biological functions of the urothelial stem cells, and (iii) the possible roles of the Wnt pathway in regulating the urothelial stem cells.