Single-cell Analysis of Human Airway Regeneration and Remodeling in Asthma – SAHARRA

SAHARRA aims to use single-cell transcriptomics to unravel the sequences of molecular events that control the balance between the distinct cell types of the airway epithelium and their deregulation in asthma.
Asthma is a chronic respiratory disorder characterized by airflow limitation, chronic inflammation and remodeling of the airway epithelium, resulting in mucus-secreting cell hyperplasia. Our understanding of epithelial specific mechanisms is largely insufficient. Yet, deciphering the epithelium-related molecular mechanisms is of paramount importance considering the pivotal roles of this tissue in the inflammatory cascade and the lack of efficient therapies in severe asthmatics.
Our strategy will draw high resolution maps of epithelial cell populations and will establish the tracing of cell trajectories upon asthma-induced tissue remodeling and after pharmacological maneuvers. This multiscale approach, ranging from fundamental to clinical research, will provide new insights into the molecular and cellular mechanisms at work in the airway epithelium during asthma.
This project is organized into 4 scientific workpackages: In WP1, we will establish single-cell transcriptomic profiles of several thousand epithelial cells derived from asthma patients and healthy controls, recovered after 28 days of air-liquid interface cell culture which, as we have previously shown, retain a “memory of disease”. We expect cell population distribution to be affected in asthma, including the already described basal and goblet cell hyperplasia. Novel data obtained in this project should implement this broad picture by revealing inter-individual heterogeneities and by identifying subpopulations at higher resolution. Based on a previous work in healthy epithelium by partner’s 1, we hypothesize that specific subpopulations of basal, club and hybrid cells may be increased in asthma samples. This will be directly tested in WP1. In WP2, we will investigate the consequences of stimulus with asthma-relevant effectors such as allergens and viruses on epithelial response of healthy and diseased samples. We wish to understand the mechanisms by which asthma samples respond differently, in terms of time course and intensity of epithelial modifications, as illustrated by the increase in goblet cell numbers. We will pay particular attention to the response produced by the novel subpopulations mentioned herein. WP3 will implement all the bioinformatics tools necessary for exploring multi-omics single-cell datasets. It will create a functional joint with existing resources, such as those set up in the context of the Human Cell Atlas, to which we are contributing. We will release a web-based tool that will allow biologists to dynamically visualize and analyze SAHARRA datasets along with HCA resources. We expect that this tool will help biologists performing powerful data integration to identify new molecular pathways involved in the development and exacerbation of severe asthma. WP4 will evaluate the functional contribution of new molecular players in the development of asthma of various severity. We will assess the impact of their invalidation on epithelial composition and/or response to asthma-relevant effectors. As such, it will lead to the discovery of new biomarkers usable for diagnosis and disease management or representing novel subsequent therapeutic targets. This project is based on the expertise of our consortium, leaders in the field of single-cell transcriptomic analysis (only French team to be selected for the Human Cell Atlas project) which is expert in 3D culture models of respiratory epithelial cells and acknowledged specialist in asthma. Patient recruitment is already possible with close collaboration with clinicians in Nice and Marseille’s hospital and specific equipment as well as the bioinformatics expertise necessary for this project is accessible through the UCA GenomiX platform, a component of the national infrastructure France Génomique.