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

摘要 柱状化生，包括Barrett‘s食道(BE)，被认为是食管癌的前驱病变。 腺癌，在过去的三十年里，发病率增加了600%。BE发生 仅在食道-胃交界处，复层的鳞状上皮转变为简单的 柱状细胞。在BE患者中，连接前移，柱状上皮扩张， 同时，在某些情况下获得肠道分化特征。值得注意的是， 化生的柱状上皮仍然存在争议。在这里，我们发现了一种新的假复层上皮 由鳞状柱状突起独特的基本祖细胞群(p63+，Krt5+，Krt7+)维持 结点(SCJ)。我们的初步数据表明，这种独特的上皮细胞是BE化生的起源。 多种小鼠模型中的上皮细胞。我们的数据进一步表明，Wnt信号促进化生改变 在SCJ。因此，我们假设包括BE在内的柱状化生起源于独特的基底 前体细胞(p63+、Krt5+、Krt7+)，这是Wnt信号促进的一个过程。我们将用以下方法检验该假设 三个具体目标：目标1：进一步测试基础祖细胞(p63+、Krt5+、Krt7+)是否为 柱状化生的起源，包括BE。目的2：检验Wnt信号促进的假设 SCJ处的柱状化生，该信号的抑制阻止了疾病的进展。目标3：树立榜样 人类BE的致病过程与人胚胎干细胞来源的柱状上皮基底祖细胞有关。我们 已经建立了一个强大的体外系统来诱导人类胚胎干细胞向 基底细胞的命运。为了达到这个目的，我们将利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。从这个项目中得出的结论将对 洞察早期BE的发病机制，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.