Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition

Carraro, Gianni; Langerman, Justin; Sabri, Shan; Lorenzana, Zareeb; Purkayastha, Arunima; Zhang, Guangzhu; Konda, Bindu; Aros, Cody J.; Calvert, Ben A.; Szymaniak, Aleks; Wilson, Emily; Mulligan, Michael J.; Bhatt, Priyanka; Lu, Junjie; Vijayaraj, Preethi; Yao, Changfu; Shia, David W.; Lund, Andrew J.; Israely, Edo; Rickabaugh, Tammy M.; Ernst, Jason; Mense, Martin; Randell, Scott H.; Vladar, Eszter K.; Ryan, Amy L.; Plath, Kathrin; Mahoney, John E.; Stripp, Barry R.; Gomperts, Brigitte N.

doi:10.1038/s41591-021-01332-7

Cited by 104 publications

(80 citation statements)

References 52 publications

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“…In addition to previously-known classifications, this work has identified new cell states and types such as the pulmonary ionocyte (Plasschaert et al 2018;Montoro et al 2018), deuterosomal cells (Ruiz García et al 2019) and a tissue migratory T helper cell population (Vieira Braga et al 2019). Respiratory system diseases such as asthma (Vieira Braga et al 2019), pulmonary fibrosis (Habermann et al 2020;Reyfman et al 2019;Adams et al 2020), chronic rhinosinusitis (Ordovas-Montanes et al 2018), cystic fibrosis (Carraro et al 2021) and the effect of smoking (Ordovas-Montanes et al 2018;Goldfarbmuren et al 2020a), have all been studied at the single cell transcriptome level.…”

Section: Introductionmentioning

confidence: 99%

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Madissoon

Oliver

Kleshchevnikov

et al. 2021

Preprint

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SummaryMultiple distinct cell types of the human lung and airways have been defined by single cell RNA sequencing (scRNAseq). Here we present a multi-omics spatial lung atlas to define novel cell types which we map back into the macro- and micro-anatomical tissue context to define functional tissue microenvironments. Firstly, we have generated single cell and nuclei RNA sequencing, VDJ-sequencing and Visium Spatial Transcriptomics data sets from 5 different locations of the human lung and airways. Secondly, we define additional cell types/states, as well as spatially map novel and known human airway cell types, such as adult lung chondrocytes, submucosal gland (SMG) duct cells, distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts and Schwann cells. Finally, we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, and B and T lineage immune cells. Using our transcriptomic data for cell-cell interaction analysis, we propose a signalling circuit that establishes and supports this niche. Overall, we provide a transcriptional and spatial lung atlas with multiple novel cell types that allows for the study of specific tissue microenvironments such as the newly defined gland-associated lymphoid niche (GALN).

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Section: Introductionmentioning

confidence: 99%

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Madissoon

Oliver

Kleshchevnikov

et al. 2021

Preprint

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“…), immunological, and physical barrier [ 20 , 51 , 52 , 53 , 54 ]. Recently, several subsets of the main epithelial cells based on different transcriptional signatures were described by single cell analyses (3 for ciliated and 5 for basal and secretory cells) [ 55 ]. The first subset of ciliated cells showed markers of cilia pre-assembly such as SPAG1 , LRRC6 , and DNAAF1 , while the second expressed markers of mature ciliated cells ( TUBA1A and TUBB4B ).…”

Section: Alterations Of the Cf Respiratory Epitheliummentioning

confidence: 99%

“…For basal cells, 5 subsets are defined: subset 1 is enriched for tumor protein P63 and cytokeratins 5 and 15; subtype 2 (proliferating basal cells) for topoisomerase II alpha and the marker of proliferation Ki-67; subset 3 (basal cells transitioning to a secretory cells) for the serpin family; subset 4 showed the AP-1 family members JUN and FOS expression; and subset 5 expressed β-catenin. Their precise roles remain unknown, and they are in similar proportions between healthy controls and patients with CF [ 55 ].…”

Section: Alterations Of the Cf Respiratory Epitheliummentioning

confidence: 99%

“…The presence of EMT and altered differentiation of epithelial cells were confirmed by more recent data that aimed to characterize the abnormal phenotype in CF bronchial epithelium, showing decreased ciliated cells number, increased goblet cells number, and increased mesenchymal markers expression [ 68 ] ( Figure 1 , unpublished data). Interestingly, the EMT sensitivity of CFTR-expressing epithelial cells was reversed by CFTR modulators [ 69 ] while in end-stage CF patients, single-cell transcriptome confirmed altered epithelial differentiation showing fewer basal cells and more cells transitioning to ciliated and secretory cells than in non-CF controls [ 55 ].…”

Section: Alterations Of the Cf Respiratory Epitheliummentioning

confidence: 99%

“…First, organoids and cell cultures of airway epithelial cells derived from patients in air–liquid condition show some features observed in vivo in CF (and in other respiratory diseases) but do not recapitulate the complexity of the airways. Notably, they differ in terms of cell populations (notably basal cell subtypes), compared to in vivo [ 55 ]. However, they are promising tools for patients with rare mutations to evaluate the response to CFTR modulators.…”

Section: Gaps In Knowledge and Perspectivesmentioning

confidence: 99%

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Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis

Gohy

Moeremans

Pilette

et al. 2021

Cells

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The respiratory epithelium represents the first chemical, immune, and physical barrier against inhaled noxious materials, particularly pathogens in cystic fibrosis. Local mucus thickening, altered mucociliary clearance, and reduced pH due to CFTR protein dysfunction favor bacterial overgrowth and excessive inflammation. We aimed in this review to summarize respiratory mucosal alterations within the epithelium and current knowledge on local immunity linked to immunoglobulin A in patients with cystic fibrosis.

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Lung regeneration: diverse cell types and the therapeutic potential

Chen,

Li,

et al. 2024

MedComm

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Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

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Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition

Cited by 104 publications

References 52 publications

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis

Lung regeneration: diverse cell types and the therapeutic potential

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