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2024-03-14

Diversity Matters: Fibroblast Heterogeneity in Pulmonary Fibrosis

News 2024-113 EN

Various tissue fibroblast types with distinct properties shape the architecture of the specialized niches of the lung (e.g. airways, alveoli, vasculature). In a significant breakthrough, a team led by Gerald Burgstaller and Herbert Schiller from Helmholtz Munich, the German Center for Lung Research (DZL) and the LMU University Hospital revealed how these fibroblast types get activated and change their activities over time during lung injury and repair. The study sheds light on the differentiation trajectories of fibroblasts and the crucial role of Secreted Frizzled Related Protein 1 (SFRP1) in modulating the phenotypic effects of transforming growth factor beta signaling. The findings were now published in the European Respiratory Journal.

Pulmonary fibrosis has no available cure to date and although two approved drugs can slow down the decline in lung function, there is a lack of means to halt or reverse the oftentimes deadly disease. An improved understanding of the pathogenesis of pulmonary fibrosis and its underlying cellular and molecular mechanisms is therefore needed for the development of targeted therapies. The authors combined genetic lineage tracing, spatial transcriptomics, time-resolved single cell transcriptomics, and functional in vitro experiments to delineate mechanisms of early stage pathogenesis of pulmonary fibrosis.

Early Activation States of Fibroblasts After Lung Injury

Using the combined insights from different data modalities the authors propose a new model of the spatiotemporal evolution of distinct fibroblast states after lung injury and the initiation of fibrosis, which is of high clinical relevance. The authors find an injury activated transitional cell state with specific cell-cell communication routes to the local niche. This transitional state is initially noninvasive and the cells differentiate towards invasive myofibroblasts through TGFβ-mediated signaling. Mechanistically, the study demonstrates how SFRP1 modulates TGFβ1-induced fibroblast invasion and RHOA pathway activity, which constitutes a novel pathway with potential for targeting fibrotic disease mediated by myofibroblasts.

In vitro fibrosis model: lung myofibroblasts in a 2D cell culture. © Gerald Burgstaller, CPC-M, Helmholtz Munich

Original publication

Mayr CH, Sengupta A, Asgharpour S, et al. Sfrp1 inhibits lung fibroblast invasion during transition to injury-induced myofibroblasts. Eur Respir J 2024; 63: 2301326 [DOI: 10.1183/ 13993003.01326-2023].

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