In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin^–Foxf1⁺ cells encompassed the stem cell antigen 1⁺CD34⁺ (Sca1⁺CD34⁺) subset of collagen 1–expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1⁺ and Foxf1^– MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1⁺Gli1⁺ MCs showed proximity to Sonic hedgehog–expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts.

中文翻译：

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转录因子 FOXF1 识别在肺同种异体移植物纤维发生中具有作用的区室不同的间充质细胞

在这项研究中，我们证明叉头盒 F1 (FOXF1) 是一种对肺发育至关重要的间充质转录因子，它保留在成人肺部支气管血管空间沿线的地形不同的间充质基质细胞群中，并确定了这种不同的胶原蛋白表达亚群细胞作为肺移植物重塑和纤维化的关键参与者。使用Foxf1-tdTomato BAC ( Foxf1 -tdTomato) 和Foxf1-tdTomato Col1a1-GFP小鼠，我们发现 Lin ^– Foxf1 ⁺细胞包含干细胞抗原 1 ⁺ CD34 ⁺ (Sca1 ⁺ CD34 ⁺) 表达胶原蛋白 1 的间充质细胞 (MC) 的子集，具有产生 CFU 和肺上皮类器官的能力。组织学上，表达 FOXF1 的 MCs 沿着导气道形成了一个 3D 网络。注意到 FOXF1 在肺泡室的 MC 中明显不存在。Bulk 和单细胞 RNA-Seq 证实了 Foxf1 ⁺和 Foxf1 ^- MCs 的不同转录特征，表达 Foxf1 的细胞由其转录因子胶质瘤相关癌基因 1 ( Gli1 ) 的高表达和整合素α 8的低表达来描绘。 Itga )，与其他表达胶原蛋白的 MCs 相比。FOXF1 ⁺ Gli1 ⁺MCs 显示接近表达 Sonic Hedgehog（Shh 表达）的支气管上皮，并且发现Foxf1和Gli1的间充质表达依赖于上皮类器官中的旁分泌 Shh 信号传导。使用鼠肺移植模型，我们显示上皮间充质 SHH/GLI1/FOXF1 串扰的失调和这种特定的支气管周围 MC 群体在慢性排斥纤维化肺同种异体移植物中的扩张。