The human respiratory airways contain a distinct multipotent secretory cell lineage that can regenerate lung alveoli
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ABSTRACT:
PROVIDER: PRJNA706420 | ENA |
REPOSITORIES: ENA
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| SRR13849786.fastq.gz | Fastqsanger.gz |
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Project description:The human lung differs substantially from its murine counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas exchange niche, forming an anatomical structure known as the respiratory airways. Due to the lack of a murine counterpart, the cellular and molecular characterization of the respiratory airways in the human lung remains an enigma. We show that human respiratory airways contain a unique secretory cell population that is distinct from cells in larger proximal airways. Stem cell modeling reveal that these respiratory airway secretory cells (RASCs) act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RASC lineage differentiation into AT2 cells is regulated, in part, by Notch signaling. In COPD, RASCs are altered transcriptionally, corresponding to abnormal AT2 cell states. These data identify a distinct progenitor in a region of the human lung not found in mouse that plays a critical role in maintaining the gas exchange compartment and is altered in chronic lung disease.
2021-12-09 | GSE168191 | GEO
Project description:The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.
| S-EPMC9297319 | biostudies-literature
Project description:Background: Loss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. Methods: pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro. Results: We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Interpretation: Loss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.
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Project description:Cardiovascular progenitors regenerate infarcted swine hearts
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Project description:The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.
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Project description:Secretory cells are the primary source of pIgR in small airways
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Project description:The microbial metagenome in airways of healthy humans
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Project description:Rationale: DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and non-malignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of COPD patients, and evaluate whether changes in gene expression are associated with these disruptions. Methods: Genome-wide methylation and gene expression analysis were performed on small airway epithelial DNA and RNA obtained from the same patient during bronchoscopy, using Illumina's Infinium HM27 and Affymetrix's Genechip Human Gene 1.0 ST arrays. To control for known effects of cigarette smoking on DNA methylation, methylation and gene expression profiles were compared between former smokers (FS) with and without COPD matched for age, pack years and years of smoking cessation. Results: Our results indicate that aberrant DNA methylation is i) a genome-wide phenomenon in small airways of patients with COPD and ii) associated with altered expression of genes and pathways important to COPD, such as the Nrf2 oxidative response pathway. Conclusions: DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Since these methylation events may underlie disease-specific gene-expression changes, their characterization is a critical first step towards the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD. Bisulphite converted DNA from small airway (airways less than <2 mm in diameter) from 38 former smokers: 15 subjects with COPD (post bronchodilator FEV1/FVC ratio <70% and FEV1 predicted M-bM-^IM-$ 80%) and 21 with normal lung function, were hybridized to the Illumina Infinium 27k Human Methylation Beadchip.
2014-02-28 | E-GEOD-55454 | biostudies-arrayexpress
Project description:Adult structures in holometabolous insects such as Drosophila are generated by groups of imaginal cells dedicated to the formation of different organs. Imaginal cells are specified in the embryo and remain quiescent until the larval stages, when they proliferate and differentiate to form organs. The Drosophila tracheal system is extensively remodeled during metamorphosis by a small number of airway progenitors. Among these, the spiracular branch tracheoblasts are responsible for the generation of the pupal and adult abdominal airways. To understand the coordination of proliferation and differentiation during organogenesis of tubular organs, we analyzed the remodeling of Drosophila airways during metamorphosis. We show that the embryonic spiracular branch tracheoblasts are multipotent cells that express the homeobox transcription factor Cut, which is necessary for their survival and normal development. They give rise to three distinct cell populations at the end of larval development, which generate the adult tracheal tubes, the spiracle and the epidermis surrounding the spiracle. Our study establishes the series of events that lead to the formation of an adult tubular structure in Drosophila.
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Project description:Placental Cdx2 cells can be isolated and utilized for cardiac regeneration in a mouse model of myocardial infarction with evidence of multipotentiality both in vitro and in vivo
2019-05-09 | PXD011783 | Pride