Regulation of mesenchymal cells by epithelial Wnt ligands

项目摘要 肺泡形成需要上皮、间充质和脉管系统的共同发育， 是支气管肺发育不良（BPD）的主要特征。这个过程依赖于精确控制 细胞间信号传导，如Fgf、Pdgf、Shh和Vegf信号传导，如最近的工作所揭示的，包括我们在 上一个补助期。另一个主要的信号通路，Wnt信号通路，在胚胎发育中被广泛研究， 在新生儿期，对肺的病理变化知之甚少，并可能涉及成人肺。此外，出版 Wnt研究集中在上皮细胞，但在很大程度上忽略了Wnt靶基因在上皮细胞内的稳健表达。 出生后间充质进一步导致我们对间充质Wnt信号传导的理解有限的是缺乏 间充质中的细胞类型的清晰度，这开始通过单细胞基因组学揭开面纱。通过 在上一次资助期间，我们发现了AT 1细胞的意想不到的信号作用， 上皮WNT配体在肺泡形成过程中特异性地向肌成纤维细胞发出信号。追求，如 提出，信号细胞（目标1），接收细胞（目标2）和疾病相关性（目标3）是 预期不仅阐明了鲜为人知的间充质Wnt信号传导，而且还建立了一个实验性的 这一范例适用于未来的肺间质研究。

PROJECT SUMMARY Alveologenesis requires co-development of the epithelium, mesenchyme, and vasculature, the failure of which is a cardinal feature of bronchopulmonary dysplasia (BPD). This process depends on precisely controlled intercellular signaling, such as Fgf, Pdgf, Shh, and Vegf signaling, as revealed by recent work including ours in the previous grant period. Another major signaling pathway, Wnt signaling, extensively studied in embryonic lungs and potentially involved in adult lungs, is poorly understood in the neonatal period. Moreover, published Wnt studies focus on epithelial cells, but largely ignore the robust expression of Wnt target genes within the postnatal mesenchyme. Further contributing to our limited understanding of mesenchymal Wnt signaling is lack of clarity on the cell types in the mesenchyme, which starts to be unveiled via single-cell genomics. By following the unexpected signaling role of AT1 cells in the previous grant period, we have obtained evidence that epithelial WNT ligands specifically signal toward myofibroblasts during alveologenesis. Pursuing, as proposed, the signaling cells (Aim 1), the receiving cells (Aim 2), and the disease relevance (Aim 3) is expected to not only elucidate the little-known mesenchymal Wnt signaling, but also establish an experimental paradigm applicable to future lung mesenchyme research.