Regulation of mesenchymal cells by epithelial Wnt ligands

项目总结 肺泡发生需要上皮、间充质和血管系统的共同发育，但失败了。 是支气管肺发育不良(BPD)的基本特征。这一过程依赖于精确的控制 细胞间信号转导，如成纤维细胞生长因子、PDGF、Shh和血管内皮生长因子信号转导，最近的工作包括我们在 上一个授权期。另一个主要的信号通路，Wnt信号，在胚胎中被广泛研究 在新生儿期，人们对肺和可能累及成人肺的疾病知之甚少。此外，还出版了 WNT的研究主要集中在上皮细胞上，但在很大程度上忽略了WNT靶基因在上皮细胞中的强劲表达 出生后间充质细胞。进一步导致我们对间充质Wnt信号的了解有限 间充质细胞类型的清晰度，这开始通过单细胞基因组学揭开面纱。通过 继AT1细胞在之前的授权期中意外地发挥信号作用后，我们获得了证据 上皮性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 建议，信号细胞(目标1)、接收细胞(目标2)和疾病相关性(目标3)是 期望不仅阐明鲜为人知的间充质Wnt信号，还将建立一种实验性的 适用于未来肺间充质研究的范式。

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.