Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.
Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.
复制标题
单细胞多组学鉴定肺泡毛细血管发育不良背后的细胞和遗传网络。
DOI：
10.1164/rccm.202210-2015oc
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发表时间：
2023
影响因子：
24.7
通讯作者：
Gu,
中科院分区：
文献类型：
--
作者：
Guo,Minzhe;Wikenheiser-Brokamp,KathrynA;Kitzmiller,JosephA;Jiang,Cheng;Wang,Guolun;Wang,Allen;Preissl,Sebastian;Hou,Xiaomeng;Buchanan,Justin;Karolak,JustynaA;Miao,Yifei;Frank,DavidB;Zacharias,WilliamJ;Sun,Xin;Xu,Yan;Gu,
Rationale:Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown.Objectives:To identify cell types, gene networks, and cell–cell interactions underlying the pathogenesis of ACDMPV.Methods:We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNAin situhybridization to identify cell types and molecular networks influenced byFOXF1in ACDMPV lungs.Measurements and Main Results:Pathogenic single-nucleotide variants and copy-number variant deletions involving theFOXF1gene locus in all subjects with ACDMPV (n= 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles forFOXF1in capillary ECs and pericytes were identified. Pathogenic variants involving theFOXF1gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell–cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV α 1 chain).Conclusions:DistinctFOXF1gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.
