Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA.
Nat Commun. 2022 Apr 19;13(1):2080. doi: 10.1038/s41467-022-29746-y.
Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1 mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1 mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.
肺内皮祖细胞 (EPCs) 对新生儿肺血管生成至关重要，代表了一般毛细血管细胞 (gCAPs) 的一个亚群。EPCs 刺激肺血管生成的分子机制尚不清楚。在此，我们使用单细胞 RNA 测序来鉴定肺 EPCs 中的 BMP9/ACVRL1/SMAD1 途径特征。Foxf1 突变小鼠（肺静脉排列不齐的肺泡毛细血管发育不良 ACDMPV 的模型）中 EPCs 的 BMP9 受体、ACVRL1 及其下游靶基因被抑制。ACDMPV 患者的肺中 ACVRL1 和其靶基因的表达减少。FOXF1 转录因子的抑制减少了 BMP9/ACVRL1 信号通路，并减少了体外血管生成。FOXF1 与 ETS 转录因子 FLI1 协同激活 ACVRL1 启动子。新生小鼠中 ACVRL1 的纳米颗粒介导沉默减少了新生儿肺血管生成和肺泡化。BMP9 的治疗恢复了 ACVRL1 缺陷和 Foxf1 小鼠的肺血管生成和肺泡化。总之，EPCs 通过 FOXF1 介导的 BMP9/ACVRL1 信号通路激活促进新生儿肺血管生成和肺泡化。
Zotero 插件
