Transgenic Ferret Models Define Pulmonary Ionocyte Diversity and Function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA977233 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24757934_1.fastq.gz | Fastqsanger.gz | |||
| SRR24757934_2.fastq.gz | Fastqsanger.gz | |||
| SRR24757935_1.fastq.gz | Fastqsanger.gz | |||
| SRR24757935_2.fastq.gz | Fastqsanger.gz | |||
| SRR24757936_1.fastq.gz | Fastqsanger.gz |
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Project description:Speciation leads to adaptive changes in organ cellular anatomy and physiology. These evolutionary changes create challenges for studying rare cell type functions that diverge between human and mice. Rare CFTR-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of novel conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO), and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models to cystic fibrosis (CF) ferrets, we demonstrate that ionocytes control airway surface liquid (ASL) absorption, secretion, pH, and mucus viscosity—leading to reduced ASL volume and impaired mucociliary clearance in CF, FOXI1-KO, and FOXI1-CreERT2::CFTRL/L ferrets. These processes were regulated by CFTR- dependent ionocyte transport of Cl– and HCO3–, as determined electrophysiologically and by single-cell imaging with a conditionally activated halide fluorescent sensor. Single-cell transcriptomics, using pulse-seq of lineage-traced ionocyte-enriched cultures, revealed three subtypes of pulmonary ionocytes with unique biologic functions and a common rare cell progenitor of ionocytes, tuft, and neuroendocrine cells. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of CF airway disease. These studies provide a road map for using conditional genetics in the first non- rodent mammal to address gene function, cell biology, and disease processes that have greater evolutionary conservation between humans and ferrets.
2023-08-01 | GSE233654 | GEO
Project description:Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.
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Project description:In the present study, we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and increase of opacification, accompanied by “honeycomb cyst-like” structures, “proximalization” of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing analysis revealed a significant shift in distal lung epithelium towards proximal epithelial phenotype. Importantly, a histopathological pattern of bronchiolization encompassing divergent atypical epithelial cells, and KRT17+/TP63+/KRT5low “basaloid-like” cells, were present in the distal fibrotic lung lesions. Trajectory analysis revealed AT2 cells transition through multiple cell-states in bleomycin injured ferret lungs, particularly AT2 to KRT8high/KRT7low/SOX4+ to eventual KRT8high/KRT7high/SFN+/TP63+/KRT5low “basaloid-like” cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside in close proximity to the ACTA2 positive myofibroblasts in fibrotic foci thereby driving fibrogenic phenotype in bleomycin injured ferret lungs. Collectively, our results provide evidence that the bleomycin ferrets can reproduce pathophysiological, cellular, and molecular features of human IPF disease, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF.
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Project description:The domestic ferret (Mustela putorius furo) has been used as animal model for decades, largely because its susceptibility to infection with a large number of pathogens such as influenza virus, SARS Corona virus and Canine distemper virus. Despite its importance for biomedical research, little is known about the genome of the M. Furo. The number of reagents for molecular and immunological analysis is thus restricted. To circumvent this, we present here a parallel sequencing effort to produce an extensive EST dataset derived from a normalized ferret cDNA library made from mRNA from ferret blood, liver, lung, spleen and brain. We produced more than 500000 sequence reads that were assembled into over 15000 partial ferret transcripts. These ESTs were combined with the available ferret sequences in the GenBank to develop a ferret specific microarray platform. Using this array, we detected tissue specific expression patterns which were confirmed by quantitative real time PCR assays and comparison to orthologous transcription profiles of mouse and human. We also present a set of 41 ferret transcript with even transcription profile across the tested tissues, indicating their usefulness as housekeeping genes. This study paves way for development of additional reagents for analysis of the ferret model. Three biological replicates of blood, lung, spleen, liver and brain was hybridized to the ferret specific microarray.
2010-09-13 | E-GEOD-19398 | biostudies-arrayexpress
Project description:Characterization of Ferret Microbiota
| PRJEB53675 | ENA
Project description:The domestic ferret (Mustela putorius furo) has been used as animal model for decades, largely because its susceptibility to infection with a large number of pathogens such as influenza virus, SARS Corona virus and Canine distemper virus. Despite its importance for biomedical research, little is known about the genome of the M. Furo. The number of reagents for molecular and immunological analysis is thus restricted. To circumvent this, we present here a parallel sequencing effort to produce an extensive EST dataset derived from a normalized ferret cDNA library made from mRNA from ferret blood, liver, lung, spleen and brain. We produced more than 500000 sequence reads that were assembled into over 15000 partial ferret transcripts. These ESTs were combined with the available ferret sequences in the GenBank to develop a ferret specific microarray platform. Using this array, we detected tissue specific expression patterns which were confirmed by quantitative real time PCR assays and comparison to orthologous transcription profiles of mouse and human. We also present a set of 41 ferret transcript with even transcription profile across the tested tissues, indicating their usefulness as housekeeping genes. This study paves way for development of additional reagents for analysis of the ferret model.
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