Diversity Matters: Fibroblast Heterogeneity in Pulmonary Fibrosis

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.