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Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling (scRNAseq)

ABSTRACT: CD44+ and CD44- negative Alveolar type 2 cells (AT2) represent distinct populations in lung fibrosis. To charecterize these cells, we isolated CD44+/- AT2s from WT mice and from fibrotic Sftpc muant lungs and performd RNA sequencing no these populations

ORGANISM(S): Mus musculus

PROVIDER: GSE273122 | GEO | 2025/07/25

REPOSITORIES: GEO

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Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling (Bulk RNA-Seq)

Project description:CD44+ and CD44- negative Alveolar type 2 cells (AT2) represent distinct populations in lung fibrosis. To charecterize these cells, we isolated CD44+/- AT2s from WT mice and from fibrotic Sftpc muant lungs and performd RNA sequencing no these populations

2025-07-25 | GSE273123 | GEO

Transcriptomic analysis of control lung alveolar type 2 cells and constitutively active-BMPR1a overexpressing alveolar type 2 cells

Project description:The Bone Morphogenetic Protein (BMP) signaling pathway functions in lung development and the regeneration of adult tracheal epithelium from basal stem cells. Here, we explore its role in the alveolar region, where Type 2 epithelial cells (AT2s) and Pdgfrα+ Type 2 - associated stromal cells (TASCs) are components of the stem cell niche. We utilize both organoid assays and in vivo alveolar regrowth after pneumonectomy (PNX) - a process requiring proliferation of AT2s and differentiation into Type 1 cells (AT1). BMP signaling is normally active in AT2s and TASCs, transiently declines post-PNX, and is restored during differentiation of AT2s to AT1s. In organoids, BMP4 inhibits AT2 proliferation, while antagonists promote AT2 self-renewal at the expense of differentiation. Gain and loss-of function genetic manipulation reveals that loss of BMP signaling in AT2s after PNX allows their self-renewal but significantly reduces differentiation into AT1s; conversely, increased BMP signaling promotes AT1 formation. The transcriptome analysis of control AT2s and AT2s overexpressing constitutively active-Bmpr1a reveals that 119 genes are upregulated more than two-fold following enhancing BMP signaling. Of these genes, 10 % are normally preferentially expressed in AT1 cells. Of the 25 genes downregulated more than two-fold, 28 % are preferentially expressed in AT2s.

2018-05-01 | GSE112431 | GEO

Expansion of SFTPC+ cells from human induced pluripotent stem cell-derived CPMhigh progenitor cells by forming alveolar organoids

Project description:Microarray analysis was performed on CPMhigh progenitor cells, P0 SFTPC+ cells, P2 SFTPC+ cells, and P5 SFTPC+ cells derived form human induced pluripotent stem cells (B2-3 SFTPC-GFP reporter hiPSCs), and parental 201B7 hiPSC-derived proximal airway epithelial cells (PAECs) and primary isolated human adult alveolar epithelial (adult AT2) cells, respectively.

2017-10-02 | GSE90591 | GEO

The single cell RNA seq of pulmonary alveolar type II (AT2) cells

Project description:The pulmonary alveolar epithelium mainly composed of two types of epithelial cells: alveolar type I (AT1) and type II (AT2) cells. AT2 cells are the alveolar stem cells, and can differentiate into AT1 cells post-pneumonectomy (PNX). Here, we found that, compared with control mice (Sftpc-CreER; Cdc42flox/+; Rosa26-mTmG) at post-PNX day 21, Cdc42 AT2 null mice (Sftpc-CreER; Cdc42flox/-; Rosa26-mTmG) at post-PNX day 21 undergone fibrotic change. By using 10X genomics “Chromium Single Cell” technology, we performed single-cell RNA-seq analyses of AT2 cells of sham treated control mice (C0), AT2 cells of control mice at post PNX day 21 (C21) , AT2 cells of sham treated Cdc42 AT2 null mice (N0), and AT2 cells of Cdc42 AT2 null mice at post PNX day 21 (N21). The study identified a specific gene signature in AT2 cells of Cdc42 AT2 null mice at post PNX day 21 which is related to the fibrosis phenotype of Cdc42 AT2 null mice.

2020-01-03 | GSE138585 | GEO

Expression of a surfactant protein C mutation impairs postnatal expansion of alveolar type 2 epithelial cells leading to permanent cell loss and decreased repair capacity in adult lungs

Project description:Mutations in the gene encoding surfactant protein C (SFTPC) are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked-in a familial, disease-associated SFTPC mutation, L188Q (L184Q in mice), into the mouse Sftpc locus. Expression of the L184Q allele (LQ) resulted in formation of an unstable, misfolded proprotein (proSP-CLQ) that was rapidly degraded by the proteasome pathway. Translation of proSP-CLQ exceeded that of proSP-CWT in neonatal AT2 cells and was associated with transient activation of oxidative stress and apoptosis leading to impaired expansion of AT2 cells during postnatal alveolarization. Consequently, adult mutant mice demonstrated a decrease in the number of AT2 cells with no effect on lung homeostasis; however, lung regeneration in response to bleomycin challenge was substantially reduced in mutant mice. Collectively, these data support the hypothesis that susceptibility to disease in adult mutant mice is established during postnatal lung development and is associated with a permanent reduction in AT2 cell numbers.

2020-08-19 | MSV000085976 | MassIVE

Expression of a surfactant protein C mutation links postnatal type 2 cell dysfunction with adult disease

Project description:Mutations in the gene encoding surfactant protein C (SFTPC) are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked-in a familial disease-associated SFTPC mutation, L188Q (L184Q in mice), into the mouse Sftpc locus. Expression of L184Q (LQ) resulted in formation of an unstable, misfolded proprotein (proSP-CLQ) that was rapidly degraded by the proteasome pathway. Importantly, expression of misfolded proSP-CLQ was associated with a decrease in AT2 cells in adult mutant mice, with no effect on lung homeostasis; however, lung regeneration in response to bleomycin challenge was substantially reduced in mutant mice. Translation of proSP-CLQ exceeded that of proSP-CWT in neonatal AT2 cells and was associated with activation of oxidative stress and apoptosis leading to impaired expansion of AT2 cells during postnatal alveolarization. Collectively, these data support the hypothesis that susceptibility to disease in adult mutant mice is established during postnatal lung development and is associated with a reduction in AT2 cell numbers.

2021-06-30 | GSE155814 | GEO

Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling (scRNAseq)

Project description:Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling (scRNAseq)

| PRJNA1140211 | ENA

Bulk transcriptomic profiling of pluripotent stem cell-derived alveolar type 2 cells (iAT2s) cultured in spheres and at air-liquid interface and human HTII-280-sorted AT2s from a pediatric and adult donor lungs cultured in spheres

Project description:We performed bulk transcriptomic profiling of pluripotent stem cell-derived alveolar type 2 cells (iAT2s) and HTII-280-sorted human AT2s cultured with CK+DCI media. We used previously described distal lung directed differentiation protocol to generate alveolar type 2 cells (iAT2s). We used the SPC2-ST-B2 (“SPC2”) line containing a SFTPC-tdTomato knock in reporter. iAT2s were cultured in 3D spheres and at air-liquid interface. Human AT2s were HTII-280-sorted from a pediatric donor lung (13 months old) and an adult, nonsmoker human lung (32 years old) and cultured as spheres in the presence of MRC5s. After deconvolution, we find that iAT2s cultured in ALI correlate more closely to primary cultured AT2s than do iAT2s cultured in 3D spheres on the basis of lung epithelial gene expression.

2022-04-30 | GSE184143 | GEO

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease

Project description:During human lung development the distal tip epithelial cells act as multipotent progenitors. From ~15 pcw (post conception weeks) the human tip epithelium retains progenitor marker expression, but also upregulates markers of the AT2 lineage. Immature AT2 cells appear in the tissue from 17 pcw. We have recently shown that 16-22 pcw epithelial tip cells can be expanded as organoids and differentiated to AT2 cells. However, the differentiated AT2 cells were not proliferative, limiting their use for functional studies and genetic manipulation. We have now developed a highly robust, efficient, and scalable culture condition (AT2 medium) that induces the differentiation of 16-22 pcw fetal lung tip cells into mature AT2 cells which grow as expandable 3D organoids. In this study, we characterise the fetal-derived AT2 cells, showing that they are stable over long-term passaging, efficiently process and secrete surfactant, and can differentiate into AT1 cells in vitro and in mouse lung transplantation assays. Forward genetic screen identifies candidate effectors of SFTPC trafficking which we validate using CRISPR interference (CRISPRi) in the AT2 organoids. We show that the trafficking of SFTPC requires ubiquitination by HECT domain E3 ligases, particularly Itch, and that their depletion phenocopies the pathological redistribution seen for the SFTPCI73T variant.

2023-08-31 | GSE237359 | GEO

XCI and sex-biased expression in AT2 cells

Project description:Significant sex differences exist for many lung pathologies, including SARS-CoV-2 related disease (COVID-19) and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Notably, Ace2, the gene encoding angiotensin-converting enzyme 2, an enzyme that plays multiple roles in SARS-CoV-2 pathogenesis, including acting as the major viral receptor, is localized on the X-chromosome. Moreover, prior work in fibroblasts suggested that Ace2 may escape X-Chromosome Inactivation (XCI), which normalizes X-lined gene expression between sexes. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express Ace2, suggesting that aberrant XCI in AT2s could potentially impact sex-biased lung pathology. To that end, we performed RNA-seq on AT2 cells isolated from 4 male and 4 female F1 mus/cast mice. Utilizing allele-specific transcriptomics, we demonstrate that about 50% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI, the highest levels reported to date. Moreover, we observe dramatic genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. Taken together, these studies support a renewed focus on AT2s as potential contributor to sex-biased differences in lung disease.

2023-01-16 | GSE203166 | GEO

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