Biology subjects

Jonker, M. R.

Publications and source records attributed to Jonker, M. R..

3 recordsLinked to original sources

bioRxiv2026

A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma

The bronchial epithelium in asthma is vulnerable to damage and has impaired barrier function, but the mechanisms by which it contributes to airway inflammation and remodelling remain unclear. Here, we dissect these epithelial and immunological disease mechanisms by establishing a comprehensive single cell atlas of the bronchial wall from 21 patients with childhood-onset asthma and 25 matched healthy controls. We identify a novel asthma-associated non-canonical epithelial differentiation trajectory in which a repair-associated KLF4+ basal cell subset differentiates into KRT13+ hillock-like cells through a proliferative KRT14+ intermediate. In vitro cultured matched primary bronchial epithelial cells show that this trajectory is retained in absence of exogenous factors. We find that IL-13 induces hillock-like cell differentiation into CEACAM5hi goblet cells, driving goblet cell metaplasia. Repair-associated basal cells and transitioning CEACAM5hi hillock-like cells strongly contribute to airway inflammation and remodelling. In turn, dendritic cells and mast cells promote a state of highly active epithelial differentiation, which shows increased multiciliated cell fate decisions, in concordance with an increase in multiciliated cell death observed in asthma. Proportions of the epithelial cells of the non-canonical differentiation trajectory are associated with clinical outcomes such as disease severity, FeNO, and small airway function.

immunology↗

bioRxiv2026

Type VI collagen is proportionally lower around airways and blood vessels in idiopathic pulmonary fibrosis

Type VI collagen (COL6) is a key extracellular matrix protein that supports matrix organization and cell-matrix interactions, yet its regulation in idiopathic pulmonary fibrosis (IPF) remains poorly understood. Here, we characterize COL6 gene expression, spatial localization, remodeling, and functional effects of COL6-derived fragments. Analysis of publicly available single-cell RNA sequencing data from 30 controls and 32 pulmonary fibrosis patients revealed higher expression of COL6A1-A6 in fibrotic lungs, predominantly in mesenchymal cells (A1: p=0.0002, A2: p=0.0005, A3: p=2.5x10-5, A5: p=0.016, A6: p=0.007). Immunohistochemical analysis of lung tissue from never-smoker (n=9), ex-smoker (n=9) controls, and IPF patients (n=12) showed extensive COL6 localization across parenchyma, airways, and vessels. The proportion of COL61 and COL62 was lower around IPF vessels (1: p<0.001, 2: p=0.012), and COL62 was lower around IPF airways (p=0.033) compared with never-smokers. Quantification of COL6 remodeling fragments in lung tissue from never-smoker (n=3), ex-smoker (n=5) controls, and IPF patients (n=10) revealed that COL6 production (PRO-C6) localized around airways and vessels but was proportionally lower in IPF airways (never-smokers: p=0.0075). In contrast, COL6 degradation (C6M) was widely distributed throughout the tissue, with lower levels in IPF (never-smokers: p=0.0008). Functionally, COL6 and PRO-C6 increased fibroblast viability (COL6: p=0.002, PRO-C6: p=0.0021), while apoptosis was unaffected. Similar trends were observed in epithelial and endothelial cells. In summary, despite increased COL6 gene expression, IPF lungs exhibited lower proportions of COL6 protein and synthesis around airways and vessels, suggesting disrupted matrix organization, altered remodeling, and pro-survival effects that may contribute to fibroblast persistence and fibrosis progression. New & NoteworthyIn this study, we revealed that IPF lungs are characterized by increased type VI collagen (COL6) gene expression but lower COL6 protein and turnover proportions around airways and blood vessels compared with controls. COL6 and a fragment associated with its production (PRO-C6) increased lung fibroblast viability. These findings highlight that pulmonary fibrotic tissue is characterized by disrupted extracellular matrix and altered tissue remodeling and suggest that COL6 may contribute to fibroblast persistence and fibrosis progression.

molecular biology↗

bioRxiv2023

Childhood-onset asthma is characterized by airway epithelial hillock-to-squamous differentiation in early life

Childhood-onset asthma is characterized by Type 2-inflammation and airway wall remodeling, but mechanisms of asthma development in the first years of life remain unclear. Here, we investigate transcriptional changes in airway wall biopsies of 22 symptomatic one year old children and relate these to asthma at school age. We demonstrate that pre-asthmatic children (n = 10) overexpressed a gene signature characteristic for an airway epithelial differentiation trajectory via hillock cells towards squamous cells (adjusted p-value 8.06e-16), whilst there was no association with gene signatures of Type 2-inflammation or eosinophil activation. Genes expressed along this trajectory are linked to an altered epithelial barrier function, innate immune activation and extracellular matrix remodeling. Functional GWAS analysis supports a causal link between childhood-onset, but not adult-onset asthma, and the hillock-squamous cell differentiation trajectory. Next, we confirmed the presence of hillock-like cells at the RNA and protein level in pediatric upper and lower airway samples. These findings identify a novel mechanism by which an aberrant airway epithelial differentiation trajectory may contribute to a pre-asthmatic state, highlighting the difference between the early origins of childhood-onset asthma and adult asthma, and point to possible new targets for the early diagnosis and treatment of asthma in the first two years of life. One Sentence SummaryRNA sequencing in bronchial biopsies from wheezing infants and children < 2 years shows evidence for an airway epithelial hillock-to-squamous differentiation pathway that marks the development of asthma.

genomics↗