Single-cell RNA-sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis; Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

2019 ◽  
Author(s):  
Rob Hynds
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cell Populations ◽  
Rna Seq ◽  
Resident Cell ◽  
Single Cell Rna Sequencing

scholarly journals Single cell RNA Sequencing Identifies G-protein Coupled Receptor 87 as a Novel Basal Cell Marker of Distal Honeycomb Cysts in Idiopathic Pulmonary Fibrosis

2021 ◽  
Author(s):  
Katharina Heinzelmann ◽  
Qianjiang Hu ◽  
Yan Hu ◽  
Evgenia Dobrinskikh ◽  
Henrik M. Ulke ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Rna Sequencing ◽  
G Protein ◽  
Potential Contribution ◽  
G Protein Coupled Receptor ◽  
Basal Progenitor ◽  
Single Cell Rna Sequencing ◽  
G Protein Coupled

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. Epithelial reprogramming and honeycomb cysts are key pathological features of IPF, however, the IPF distal bronchiole cell subtypes and their potential contribution to IPF development and progression still remain poorly characterized. Here, we utilized single-cell RNA sequencing on enriched EpCAM+ cells of the distal IPF and Donor lung. Using the 10x Genomics platform, we generated a dataset of 47,881 cells and found distinct cell clusters, including rare cell types, such as suprabasal cells recently reported in the healthy lung. We identified G-protein coupled receptor (GPR) 87 as a novel surface marker of distal Keratin (KRT)5+ basal cells. GPR87 expression was localized to distal bronchioles and honeycomb cysts in IPF in situ by RNA Scope and immunolabeling. Modulation of GPR87 in primary human bronchial epithelial cells cultures resulted in impaired airway differentiation and ciliogenesis. Thus, GPR87 is a novel marker and potentially druggable target of KRT5+ basal progenitor cells likely contributing to bronchiole remodeling and honeycomb cyst development in IPF.

scholarly journals Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

2020 ◽  
Author(s):  
Emmi Helle ◽  
Minna Ampuja ◽  
Alexandra Dainis ◽  
Laura Antola ◽  
Elina Temmes ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Tissue Growth ◽  
Cell Phenotype ◽  
Cell Populations ◽  
Pump System ◽  
Single Cell Rna Sequencing

AbstractRationaleCell-cell interactions are crucial for the development and function of the organs. Endothelial cells act as essential regulators of tissue growth and regeneration. In the heart, endothelial cells engage in delicate bidirectional communication with cardiomyocytes. The mechanisms and mediators of this crosstalk are still poorly known. Furthermore, endothelial cells in vivo are exposed to blood flow and their phenotype is greatly affected by shear stress.ObjectiveWe aimed to elucidate how cardiomyocytes regulate the development of organotypic phenotype in endothelial cells. In addition, the effects of flow-induced shear stress on endothelial cell phenotype were studied.Methods and resultsHuman induced pluripotent stem cell (hiPSC) -derived cardiomyocytes and endothelial cells were grown either as a monoculture or as a coculture. hiPS-endothelial cells were exposed to flow using the Ibidi-pump system. Single-cell RNA sequencing was performed to define cell populations and to uncover the effects on their transcriptomic phenotypes. The hiPS-cardiomyocyte differentiation resulted in two distinct populations; atrial and ventricular. Coculture had a more pronounced effect on hiPS-endothelial cells compared to hiPS-cardiomyocytes. Coculture increased hiPS-endothelial cell expression of transcripts related to vascular development and maturation, cardiac development, and the expression of cardiac endothelial cell -specific genes. Exposure to flow significantly reprogrammed the hiPS-endothelial cell transcriptome, and surprisingly, promoted the appearance of both venous and arterial clusters.ConclusionsSingle-cell RNA sequencing revealed distinct atrial and ventricular cell populations in hiPS-cardiomyocytes, and arterial and venous-like cell populations in flow exposed hiPS-endothelial cells. hiPS-endothelial cells acquired cardiac endothelial cell identity in coculture. Our study demonstrated that hiPS-cardiomoycytes and hiPS-endothelial cells readily adapt to coculture and flow in a consistent and relevant manner, indicating that the methods used represent improved physiological cell culturing conditions that potentially are more relevant in disease modelling. In addition, novel cardiomyocyte-endothelial cell crosstalk mediators were revealed.

scholarly journals A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages

2019 ◽  
Vol 55 (1) ◽  
pp. 1900646 ◽  
Author(s):  
Nikita Joshi ◽  
Satoshi Watanabe ◽  
Rohan Verma ◽  
Renea P. Jablonski ◽  
Ching-I Chen ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Rna Sequencing ◽  
Single Molecule ◽  
Alveolar Macrophages ◽  
Lineage Tracing ◽  
Single Cell Rna Sequencing ◽  
Pharmacological Blockade ◽  
Macrophage Colony ◽  
Druggable Targets

Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms.We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis.Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.

scholarly journals Single-Cell RNA Sequencing in Human Retinal Degeneration Reveals Distinct Glial Cell Populations

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 438 ◽  
Author(s):  
Andrew P. Voigt ◽  
Elaine Binkley ◽  
Miles J. Flamme-Wiese ◽  
Shemin Zeng ◽  
Adam P. DeLuca ◽  
...  
Keyword(s):  
Single Cell ◽  
Retinal Degeneration ◽  
Rna Sequencing ◽  
Glial Cell ◽  
Glial Cells ◽  
Peripheral Retina ◽  
Cell Populations ◽  
Specific Gene ◽  
Autoimmune Retinopathy ◽  
Single Cell Rna Sequencing

Degenerative diseases affecting retinal photoreceptor cells have numerous etiologies and clinical presentations. We clinically and molecularly studied the retina of a 70-year-old patient with retinal degeneration attributed to autoimmune retinopathy. The patient was followed for 19 years for progressive peripheral visual field loss and pigmentary changes. Single-cell RNA sequencing was performed on foveal and peripheral retina from this patient and four control patients, and cell-specific gene expression differences were identified between healthy and degenerating retina. Distinct populations of glial cells, including astrocytes and Müller cells, were identified in the tissue from the retinal degeneration patient. The glial cell populations demonstrated an expression profile consistent with reactive gliosis. This report provides evidence that glial cells have a distinct transcriptome in the setting of human retinal degeneration and represents a complementary clinical and molecular investigation of a case of progressive retinal disease.

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