Role of interdigitating secretory cells in regulation of intestinal stem cells during development

摘要/摘要 虽然成人肠道干细胞巢的结构已经很明确，但几乎没有。 了解未成熟干细胞生态位的结构和调节。在成人中 哺乳动物的隐窝，专用干细胞被称为隐窝基柱(CBC) 细胞由小肠中交错的Paneth细胞和一种亚型的 大肠内的杯状细胞。在这里，我们认为未成熟的干细胞 隔室由类似潘氏细胞和杯状细胞的细胞调节，即 调节未成熟干细胞的生长和向成体转化 结构。利用外部开发和透明度的优势 斑马鱼模型系统为了操纵和可视化发育中的肠道，我们识别 未成熟干细胞室内的调节细胞，在折叠处分化 从胚胎发育末期开始，一直延续到幼体阶段。 初步数据表明，这些细胞参与了上皮细胞的负性调节 有两个不同的组，一个组在 幼虫期的前半部分，随着肠道的成熟而形成的第二组 成人结构。在目标1中，我们将专注于破坏这些细胞的功能，以 确定它们在调节发育中的干细胞结构中的作用 通向成体肠道干细胞的成熟室。在……里面 目的2我们将确定已鉴定的调节细胞是否调节上皮细胞 通过调节Wnt途径促进细胞增殖。最后，在目标3中，我们将确定 甲状腺激素在调节细胞组的分化中起作用 随着肠道的成熟分化为成体结构。总而言之，这些研究将 识别控制未成熟干细胞生长的网络的新特征 当它成熟进入成体结构时，它会进入隔室。从长远来看，这项工作具有 有可能阐明由先天缺陷引起的肠道疾病 建立肠上皮干细胞隔室过程中的错误。

Summary/Abstract While the structure of the adult intestinal stem cell niche has become well defined, little is know about the structure and regulation of the immature stem cell niche. In the adult mammalian crypt, dedicated stem cells are referred to as Crypt Base Columnar (CBC) cells are regulated by interdigitated Paneth cells in the small intestine and a subtype of goblet cells in the large intestine. Here we propose that the immature stem cell compartment is regulated by cells analogous to the Paneth and goblet cells, that regulate growth and transformation of an immature stem cell niche into the adult structure. Using the advantages of external development and transparency of the zebrafish model system to manipulate and visualize the developing intestine, we identify regulatory cells within the immature stem cell compartment, which differentiate at the fold base beginning at the end of embryogenesis and continuing through juvenile phase. Preliminary data indicates that these cells are involved negative regulation of epithelial proliferation and there are two different groups, one group that differentiates during the first half of juvenile period and a second group that forms as the intestine matures to the adult structure. In Aim 1 we will focus on disrupting the function of these cells to determine their role in regulation of the architecture of the developing stem cell compartment leading up to maturation of the adult intestinal stem cell compartment. In Aim 2 we will determine whether the identified regulatory cells modulate epithelial proliferation by modulating the Wnt pathway. Finally, in Aim 3, we will determine whether thyroid hormone plays a role in differentiation of the group of regulatory cells that differentiates as the intestine matures to the adult structure. Together, these studies will identify new features of the network controlling growth of the immature stem cell compartment as it matures into the adult structure. In the long term, this work has the potential to shed light on intestinal diseases resulting from congenital defects due to errors during establishment of the intestinal epithelial stem cell compartment.