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Mayr CH, Sengupta A, Asgharpour S, Ansari M, Pestoni JC, Ogar P, Angelidis I, Liontos A, Rodriguez-Castillo JA, Lang NJ, Strunz M, Porras-Gonzalez D, Gerckens M, De Sadeleer LJ, Oehrle B, Viteri-Alvarez V, Fernandez IE, Tallquist M, Irmler M, Beckers J, Eickelberg O, Stoleriu GM, Behr J, Kneidinger N, Wuyts WA, Wasnick RM, Yildirim AÖ, Ahlbrecht K, Morty RE, Samakovlis C, Theis FJ, Burgstaller G, Schiller HB
Eur. Respir. J. 63 (2) - [2024-02-00; online 2024-02-08]
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. 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. 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. 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.
PubMed 38212077
DOI 10.1183/13993003.01326-2023
Crossref 10.1183/13993003.01326-2023
pmc: PMC10850614
pii: 13993003.01326-2023