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

总结/摘要 虽然成体肠干细胞龛的结构已经很好地定义， 了解未成熟干细胞龛的结构和调节。在成人 在哺乳动物隐窝中，专用干细胞被称为隐窝基底柱状细胞（CBC）。 细胞由小肠中的交叉指状潘氏细胞调节， 大肠中的杯状细胞。在这里，我们提出，未成熟的干细胞 隔室由类似于潘氏细胞和杯状细胞的细胞调节， 调节未成熟干细胞小生境的生长和向成人的转化 结构利用外部开发和透明化的优势， 斑马鱼模型系统来操纵和可视化发育中的肠道，我们确定了 未成熟干细胞区室中的调节细胞，其在褶皱处分化 从胚胎发生末期开始并持续到幼年期的基部。 初步数据表明，这些细胞参与上皮细胞的负调控， 有两个不同的群体，一个群体在增殖过程中分化， 第一组是少年时期的前半部分，第二组是随着肠道成熟而形成的。 成人结构在目标1中，我们将专注于破坏这些细胞的功能， 确定它们在调节发育中的干细胞结构中的作用 肠干细胞的成熟是指肠干细胞的成熟。在 目的2：我们将确定所鉴定的调节细胞是否调节上皮细胞的生长， 通过调节Wnt通路来抑制增殖。最后，在目标3中，我们将确定 甲状腺激素在调节细胞群的分化中起作用， 随着肠道发育成熟形成成体结构而分化。这些研究将 识别控制未成熟干细胞生长的网络的新特征 当它成熟为成年人的结构时，从长远来看，这项工作具有 可能揭示肠道疾病造成的先天性缺陷，由于 在建立肠上皮干细胞区室的过程中出现错误。

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.