Neuroendocrinology of the lung revealed by single cell RNA sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE191178 | GEO | 2022/12/06
REPOSITORIES: GEO
Similar Datasets
Project description:Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs) which express core PNEC markers, genes therby recapitulating known functions of primary PNECs. Single-cell RNA sequencing (scRNA-seq) of these iPNEC revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.
2020-05-13 | GSE146990 | GEO
Project description:Limiting fluid in lung is critical for efficient gas exchange. Here we discovered a mechanism of neuropeptidergic control of lung fluid balance by pulmonary neuroendocrine cells (PNECs), potent sensors of chemical and mechanical cues. We studied the first animal model of neuroendocrine cell hyperplasia of infancy (NEHI), which faithfully recapitulated patient phenotypes including PNEC hyperplasia and impaired gas exchange. Double mutants showed that increased PNECs and excess PNEC products such as CGRP are responsible for poor gas exchange, acting through downregulating endothelial junctions, increasing vessel leakage and fluid accumulation. Endothelium-specific inactivation of CGRP receptor, or treatment with CGRP receptor antagonist reduced fluid and improved gas exchange. In lungs with acute respiratory distress syndrome (ARDS), including those caused by COVID-19, there was a striking increase of CGRP-expressing PNECs. These findings raise the possibility that increased neuropeptides would contribute to excess extravascular lung fluid and antagonizing their function may improve gas exchange.
2022-02-18 | GSE171907 | GEO
Project description:Large numbers of cells are generally required for quantitative global proteome profiling due to the significant surface adsorption losses associated with sample processing. Such bulk measurement obscures important cell-to-cell variability (cell heterogeneity) and makes proteomic profiling impossible for rare cell populations, such as circulating tumor cells (CTCs) and early metastatic cells. Herein we report a facile mass spectrometry (MS)-based single-cell proteomics method that capitalizes on a MS-compatible nonionic surfactant, n-Dodecyl-β-D-maltoside, for greatly reducing the surface adsorption losses by ~20-fold for effective single-tube processing of single cells, thus significantly improving detection sensitivity for single-cell proteomic analysis. With standard MS platforms, the method allows for the first time precise, label-free, reliable quantification of hundreds of proteins from single human cells in a simple, convenient manner. When applied to a patient CTC-derived xenograft (PCDX) model, the method can reveal distinct protein signatures between primary tumor cells and early metastases to the lungs at the single-cell resolution. The approach paves the way for routine, precise quantitative single-cell proteomic analysis.
2021-06-07 | PXD017075 | JPOST Repository
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171918 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171917 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171916 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171915 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171914 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE185413 | GEO
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