Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV)

Minzhe Guo¹, Kathryn A. Wikenheiser-Brokamp¹, Joseph A. Kitzmiller¹, Cheng Jiang¹, Guolun Wang¹, Allen Wang², Sebastian Preissl², Yifei Miao¹, David B. Frank³, William J. Zacharias¹, Xin Sun², Yan Xu¹, Mingxia Gu¹, Pawel Stankiewicz⁴, Vladimir V. Kalinichenko¹, Jennifer A. Wambach⁵, Jeffrey A. Whitsett¹

¹Cincinnati Children's Hospital Medical Center, ²University of California, San Diego, ³Children’s Hospital of Philadelphia, ⁴Baylor College of Medicine, ⁵Washington University School of Medicine, ^*Corresponding author

How to explore data (tutorial) | How to cite

Description 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. To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV. We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA in situ hybridization to identify cell types and molecular networks influenced by FOXF1 in ACDMPV lungs. Pathogenic single-nucleotide variants and copy-number variant deletions involving the FOXF1 gene 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 for FOXF1 in capillary ECs and pericytes were identified. Pathogenic variants involving the FOXF1 gene 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). Distinct FOXF1 gene 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.

Dataset ID LMEX0000004408

Assay Type Single-cell RNA-seq

Organism Human

Stages Neonate | Infant | Child

Cell Count 17836

Technology 10x Genomics Chromium Single Cell Gene Expression

Reference Guo, et al. (2023)

File	Description	Size
ACDMPV_library_metadata.tsv	Library metadata for the 5 libraries, one row each. Carries the donor, sex, age, age range, reported ethnicity, disease, anatomic region, cause of death and the nuclei each library contributes. The Samples tab shows only the fourteen columns the site defines for a human sample, so this file carries the rest.	0.9 KB
ACDMPV_release_counts.h5ad	Release object for this study, HDF5 AnnData, gzip compressed. 17,836 nuclei x 34,659 genes over 60 CellRef2.0 v7 cell states and 5 libraries. X holds RAW INTEGER COUNTS, not a normalized matrix. obs carries the CellRef2.0 v7 cell state, its short name, the library, the donor age, age range and reported ethnicity, and the cellHarmony alignment score of every nucleus. obsm carries the UMAP. The site viewers read a log2 counts per ten thousand matrix rebuilt from these counts.	132.4 MB

LungMAP ID	Alt ID	Species	Sex	Race	Age	Age Group	Health Status
LMSPACD0000001	ACD1	Homo sapiens	Male	European	2 years	1-4 years	alveolar capillary dysplasia with misalignment of pulmonary veins
LMSPACD0000002	ACD2	Homo sapiens	Male	European	3.5 years	1-4 years	alveolar capillary dysplasia with misalignment of pulmonary veins
LMSPACD0000003	ACD3	Homo sapiens	Male	Hispanic or Latin American	9 years	5-9 years	alveolar capillary dysplasia with misalignment of pulmonary veins
LMSPACD0000004	ACD4	Homo sapiens	Male	European	5 years	5-9 years	alveolar capillary dysplasia with misalignment of pulmonary veins
LMSPACD0000005	ACD5	Homo sapiens	Male	European	1 years	1-4 years	alveolar capillary dysplasia with misalignment of pulmonary veins