Sfrp1 inhibits lung fibroblast invasion during transition to injury-induced myofibroblasts

Christoph H. Mayr, Arunima Sengupta, Sara Asgharpour, Meshal Ansari, Jeanine C. Pestoni, Paulina Ogar, Ilias Angelidis, Andreas Liontos, José Alberto Rodriguez-Castillo, Niklas J. Lang, Maximilian Strunz, Diana Porras-Gonzalez, Michael Gerckens, Laurens J. De Sadeleer, Bettina Oehrle, Valeria Viteri-Alvarez, Isis E. Fernandez, Michelle Tallquist, Martin Irmler, Johannes BeckersOliver Eickelberg, Gabriel Mircea Stoleriu, Jürgen Behr, Nikolaus Kneidinger, Wim A. Wuyts, Roxana Maria Wasnick, Ali Önder Yildirim, Katrin Ahlbrecht, Rory E. Morty, Christos Samakovlis, Fabian J. Theis, Gerald Burgstaller, Herbert B. Schiller

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background Fibroblast-to-myofibroblast conversion is a major driver of tissue remodelling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet their specific activation states and phenotypic trajectories during injury and repair have remained unclear. Methods We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-sequencing and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in idiopathic pulmonary fibrosis patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to transforming growth factor (TGF)β1. Measurements and main results We discovered a transitional fibroblast state characterised by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage-specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. TGFβ1 downregulated SFRP1 in noninvasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss-of-function studies we showed that SFRP1 modulates TGFβ1-induced fibroblast invasion and RHOA pathway activity. Conclusions Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1-driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation.

Original languageEnglish
Article number2301326
JournalEuropean Respiratory Journal
Volume63
Issue number2
DOIs
StatePublished - 1 Feb 2024

Fingerprint

Dive into the research topics of 'Sfrp1 inhibits lung fibroblast invasion during transition to injury-induced myofibroblasts'. Together they form a unique fingerprint.

Cite this