Biology subjects

Timens, W.

Publications and source records attributed to Timens, W..

22 records · Page 2Linked to original sources

bioRxiv2019

A cellular census of healthy lung and asthmatic airway wall identifies novel cell states in health and disease

Human lungs enable efficient gas exchange, and form an interface with the environment which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in health. We report location-dependent airway epithelial cell states, and a novel subset of tissue-resident memory T cells. In lower airways of asthma patients, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report presence of pathogenic effector Th2 cells in asthma, and find evidence for type-2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identify a shift from airway structural cell communication in health to a Th2-dominated interactome in asthma.

immunology↗

bioRxiv2018

Characterizing smoking-induced transcriptional heterogeneity in the human bronchial epithelium at single-cell resolution

The human bronchial epithelium is composed of multiple, distinct cell types that cooperate to perform functions, such as mucociliary clearance, that defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, the precise effects of this exposure on specific cell types are not well-understood. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never- and six current smokers. Unsupervised analyses identified thirteen cell clusters defined by unique combinations of nineteen distinct gene sets. Expression of a set of toxin metabolism genes localized to ciliated cells from smokers. Smoking-induced airway remodeling was characterized by a loss of club cells and extensive goblet cell hyperplasia. Finally, we identified a novel peri-goblet epithelial subpopulation in smokers that expressed a marker of bronchial premalignant lesions. Our data demonstrates that smoke exposure drives a complex landscape of cellular and molecular alterations in the human bronchial epithelium that may contribute to the onset of smoking-associated lung diseases.

genomics↗

bioRxiv2017

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations

We collated 129 non-overlapping risk loci for chronic obstructive pulmonary disease (COPD) from the GWAS literature. Using recent and complementary integrative genomics approaches, combining GWAS and lung eQTL results, we identified 12 novel COPD loci and corresponding causal genes. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci as well as for four sub-genome-wide significant COPD risk loci derived from the largest GWAS on COPD. Mapping causal genes in lung tissue represents an important contribution on the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.

genomics↗

bioRxiv2017

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{middle dot}8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 and PLAU. Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

genetics↗