Barrett's esophagus and progenitor cells at the squamous-columnar junction

总结 柱状化生，包括巴雷特食管（BE），被认为是食管癌的前驱病变， 腺癌，在过去三十年中发病率增加了600%。BE发生 仅在胃-胃交界处，其中复层鳞状上皮转变为单层鳞状上皮， 柱状细胞在BE患者中，连接向前移动，柱状上皮扩张， 同时部分病例获得肠分化特征。值得注意的是， 化生柱状上皮仍有争议。在这里，我们确定了一个新的假复层上皮 由鳞状-柱状细胞中独特的基底祖细胞群（p63+，KRT 5+，KRT 7+）维持 交叉点（SCJ）。我们的初步数据表明，独特的上皮细胞作为起源BE化生 在多种小鼠模型中的上皮。我们的数据进一步表明，Wnt信号促进化生变化， 在SCJ。因此，我们假设包括BE在内的柱状上皮化生来源于独特的基底膜。 祖细胞（p63+、KRT 5+、KRT 7+）的细胞周期，这是由Wnt信号传导促进的过程。我们将测试假设与 三个具体目的：目的1：为了进一步测试基底祖细胞（p63+，KRT 5+，KRT 7+）是细胞- 柱状化生（包括BE）的起源。目的2：验证Wnt信号促进细胞凋亡的假设。 在SCJ柱状化生和抑制这种信号传导阻断疾病的进展。目标3：建模 人BE致病过程与hESC衍生的柱状上皮基底祖细胞。我们 已经建立了一个强大的体外系统，以诱导人类胚胎干细胞分化为 基底细胞命运在这个目标中，我们将使用这个系统来理解驱动异常的机制， BE发育过程中基底细胞的分化。该项目的研究结果将有助于 深入了解早期BE发病机制，并为治疗提供潜在的治疗靶点。

SUMMARY Columnar metaplasia, including Barrett’s esophagus (BE), is considered a precursor lesion of esophageal adenocarcinoma which has seen a 600% fold increase in incidence over the last three decades. BE occurs exclusively at the esophageal-gastro junction where the stratified squamous epithelium transitions into simple columnar cells. In patients with BE the junction moves anteriorly and the columnar epithelium is expanded, meanwhile gaining intestinal differentiation characteristics in some cases. Significantly, the cell-of-origin of the metaplastic columnar epithelium remains controversial. Here, we identify a novel pseudostratified epithelium maintained by a unique basal progenitor cell population (p63+, KRT5+, KRT7+) at the squamous-columnar junction (SCJ). Our preliminary data suggest that the unique epithelium serves as the origin for BE metaplastic epithelium in multiple mouse models. Our data further indicate that Wnt signaling promotes metaplastic changes at the SCJ. We therefore hypothesize that columnar metaplasia including BE is derived from the unique basal progenitor cells (p63+, KRT5+, KRT7+), a process promoted by Wnt signaling. We will test the hypothesis with three specific aims: Aim 1: To further test that the basal progenitor cells (p63+, KRT5+, KRT7+) are the cells- of-origin for columnar metaplasia including BE. Aim 2: To test the hypothesis that Wnt signaling promotes columnar metaplasia at the SCJ and that inhibition of this signaling blocks disease progression. Aim 3: To model the human BE pathogenic process with hESC-derived basal progenitor cells of the columnar epithelium. We have established a robust in vitro system to induce the differentiation of human embryonic stem cells towards basal cell fate. In this aim we will use this system to understand the mechanism driving the abnormal differentiation of basal cells during BE development. Together findings from this project will contribute important insights into early BE pathogenesis and provide potential therapeutic targets for treatment.