The signaling role of alveolar type 1 cell-derived Wnt ligands during alveologenesis

项目总结 尽管多年来产生表面活性物质的肺泡2型细胞一直是关注的焦点，但肺泡1型 (AT1)细胞是覆盖90%气体交换表面积的邻近肺上皮细胞。我们发现 AT1细胞不仅仅是一种被动结构，因为它们表达VEGFA并向血管系统发出信号。我们 还发现AT1细胞表达Wnt配体。有趣的是，培养的肺成纤维细胞在WNT3a上增殖 刺激和肺肌成纤维细胞广泛表达规范的Wnt靶基因Axin2。这导致了我们的 假设AT1细胞通过Wnt配体向肺肌成纤维细胞发出信号。我们将调查以下要求： AT1衍生的Wnt配体用于肺泡形成过程中的肺肌成纤维细胞(Aim 1)，上皮-间充质 信号机制(AIM 2)，以及Wnt介导的AT1和肺成纤维细胞之间的串扰 实验BPD模型(目标3)。这项研究的成功完成将揭示AT1的新信号作用 细胞，并阐明肺间充质细胞类型，从而代表着朝着我们的长期目标迈出的第一步

PROJECT SUMMARY Although surfactant producing alveolar type 2 cells have been the focus for many years, the alveolar type 1 (AT1) cells are the neighboring lung epithelial cells that cover >90% gas exchange surface area. We found AT1 cells are more than a passive structure because they express VEGFA and signal to the vasculature. We also found AT1 cells express Wnt ligands. Interestingly, cultured lung fibroblasts proliferate upon WNT3A stimulation and lung myofibroblasts express widely canonical Wnt target gene, Axin2. This led to our hypothesis that AT1 cells signal lung myofibroblasts via Wnt ligands. We will investigate the requirement of AT1-derived Wnt ligands for lung myofibroblasts during alveologenesis (aim 1), the epithelial-mesenchymal signaling mechanism (aim 2), and the Wnt-mediated crosstalk between AT1 and lung myofibroblasts in an experimental BPD models (aim 3). Successful completion of this study will reveal a new signaling role of AT1 cells and elucidate lung mesenchymal cell types, thereby representing a first step toward our long-term goal of unraveling epithelial-mesenchymal crosstalk during alveologenesis and BPD pathogenesis.