Epithelial-mesenchymal crosstalk in intestinal polyp formation

哺乳动物小肠上皮-间充质相互作用调控干细胞 细胞增殖和分化之间精确平衡的动力学。间充质细胞，特别是 成纤维细胞分泌信号以调节上皮细胞，例如用于上皮生长的Wnt和用于上皮生长的Bmp。 分化然而，成纤维细胞本身是如何调节的仍然是未知的。研究成纤维细胞生物学 是至关重要的，因为成纤维细胞可以驱动肠息肉病，这是一种常见的胃肠道疾病， 过度增殖与肠癌变风险升高有关。人类幼年性息肉病与遗传性 混合性息肉病综合征与导致BMP信号丢失的种系突变有关。尽管 作为息肉中上皮过度生长的一个共同特征，小鼠研究表明， 来自成纤维细胞而不是来自肠上皮的信号足以驱动息肉形成。的机制 成纤维细胞的BMP信号丢失驱动发展中的息肉中不受控制的上皮生长， 不清楚总体目标是（i）确定上皮细胞的潜在成纤维细胞驱动机制， Aim 1中BMP信号丢失后的过度增殖，以及（ii）定义BMP信号对成纤维细胞的作用 目标2中身份规范和维护。为了诱导息肉形成，诱导型Bmp信号丢失- 利用通过过表达BMP拮抗剂头蛋白的功能小鼠模型。惊人的是，在三个 在BMP信号抑制的30天内，肠首先经历结构变化，即异位组织折叠， 不涉及上皮细胞过度增殖。相反，上皮细胞增殖仅在几周后增加， Bmp信号丢失。我的发现是第一个提示组织结构在调节干细胞中的作用 动态和上皮内环境稳定。中心假设是，肠上皮细胞的特定亚群的改变可能是一个重要因素。 成纤维细胞破坏局部组织结构，导致息肉形成。长期目标是了解 空间分离的独特成纤维细胞亚型调节组织稳态并促成疾病 发病机制正如我的初步数据表明，成纤维细胞错误定位和积累向茎 细胞，与异位折叠形成一致，Aim 1将检查成纤维细胞分泌的Wnt配体的变化 在上皮内的分布，以及这些变化是否导致发展中的息肉中的上皮过度生长。 这一目标将加深我们对上皮细胞和小生境之间失调串扰的基础知识 肠道发病机制的参与者。Aim 2将采用空间转录组学方法来研究 息肉发生和发展过程中成纤维细胞基因表达谱和定位的Bmp信号丢失。 它将揭示Bmp信号在指定/维持成纤维细胞亚型身份和空间分布方面的要求。 在肠道内稳态中的分布，并且当被破坏时，在发育过程中驱动上皮过度增殖。 息肉这个项目的完成将推进我们对成纤维细胞调控和干细胞生态位的认识 动力学，这可能导致在预防/治疗肠癌的新的靶细胞类型的鉴定。

Project Summary Epithelial-mesenchymal interactions within the mammalian small intestine regulate stem cell dynamics for accurate balance between cell proliferation and differentiation. Mesenchymal cells, particularly fibroblasts, secrete signals to regulate epithelial cells, such as Wnt for epithelial growth and Bmp for epithelial differentiation. However, how fibroblasts themselves are regulated remains unknown. Studying fibroblast biology is critical, as fibroblasts can drive intestinal polyposis, which is a common gastrointestinal condition with epithelial hyperproliferation linked to elevated risk of intestinal carcinogenesis. Human juvenile polyposis and hereditary mixed polyposis syndromes are associated with germline mutations that lead to Bmp signaling loss. Despite common feature of epithelial overgrowth in polyps, mouse studies have demonstrated that specific loss of Bmp signaling from fibroblasts, not from intestinal epithelium, is sufficient to drive polyp formation. The mechanisms by which Bmp signaling loss from fibroblasts drives uncontrolled epithelial growth in developing polyps remain unclear. The overall objectives are to (i) determine the underlying fibroblast-driven mechanisms of epithelial hyperproliferation upon Bmp signaling loss in Aim 1, and to (ii) define the role of Bmp signaling to fibroblast identity specification and maintenance in Aim 2. To induce polyp formation, an inducible Bmp signaling loss-of- function mouse model through overexpression of the Bmp antagonist Noggin is utilized. Strikingly, within three days of Bmp signaling inhibition, the intestine first undergoes an architectural change, an ectopic tissue fold, that does not involve epithelial hyperproliferation. Rather, epithelial proliferation only increases after several weeks of Bmp signaling loss. My finding is the first to suggest the role of tissue architecture in regulating stem cell dynamics and epithelial homeostasis. The central hypothesis is that alterations in specific subset(s) of intestinal fibroblasts disrupt local tissue architecture, resulting in polyp formation. The long-term goal is to understand how spatially segregated, unique fibroblast subtypes regulate tissue homeostasis and contribute to disease pathogenesis. As my preliminary data demonstrate that fibroblasts mislocalize and accumulate towards stem cells, coinciding with ectopic fold formation, Aim 1 will examine changes in fibroblast-secreted Wnt ligand distribution within the epithelium, and whether these changes result in epithelial overgrowth in developing polyps. This aim will deepen our foundational knowledge on dysregulated crosstalk between epithelial cells and niche players in intestinal pathogenesis. Aim 2 will employ a spatial transcriptomic approach to examine the effects of Bmp signaling loss to fibroblast gene expression profiles and localization during polyp initiation and progression. It will reveal the requirements for Bmp signaling in specifying/maintaining fibroblast subtype identity and spatial distribution in intestinal homeostasis, and that when disrupted, drives epithelial hyperproliferation in developing polyps. Completion of this project will advance our knowledge on fibroblast regulation and stem cell niche dynamics, which could lead to the identification of novel target cell types in preventing/treating intestinal cancers.