NO-sensitive guanylyl cyclase discriminates pericyte-derived interstitial from intra-alveolar myofibroblasts in murine pulmonary fibrosis

• Published in: Respiratory research 2023-06, Vol.24 (1), p.167-167, Article 167
• Main Authors: Aue, Annemarie, Englert, Nils, Harrer, Leon, Schwiering, Fabian, Gaab, Annika, König, Peter, Adams, Ralf, Schmidtko, Achim, Friebe, Andreas, Groneberg, Dieter
• Format: Article
• Language: English
• Subjects: Alveoli; Animals; Antibodies; Bleomycin; Care and treatment; Chloride; Collagen; Collagen - metabolism; Diagnosis; Dosage and administration; Extracellular matrix; Fibrosis; Genetic aspects; Genetic engineering; Guanylate cyclase; Guanylate Cyclase - metabolism; Guanylyl cyclase; Health aspects; Hydroxyproline; Immunofluorescence; Injury prevention; Lung diseases; Lungs; Methods; Mice; Myofibroblasts; Myofibroblasts - metabolism; Nitric oxide; Pericytes; Pericytes - metabolism; Properties; Pulmonary fibrosis; Pulmonary Fibrosis - metabolism; Smooth muscle; Sodium; Tamoxifen; Transgenic mouse
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-023-02479-2

The origin of αSMA-positive myofibroblasts, key players within organ fibrosis, is still not fully elucidated. Pericytes have been discussed as myofibroblast progenitors in several organs including the lung. Using tamoxifen-inducible PDGFRβ-tdTomato mice (PDGFRβ-CreER ; R26tdTomato) lineage of lung pericytes was traced. To induce lung fibrosis, a single orotracheal dose of bleomycin was given. Lung tissue was investigated by immunofluorescence analyses, hydroxyproline collagen assay and RT-qPCR. Lineage tracing combined with immunofluorescence for nitric oxide-sensitive guanylyl cyclase (NO-GC) as marker for PDGFRβ-positive pericytes allows differentiating two types of αSMA-expressing myofibroblasts in murine pulmonary fibrosis: (1) interstitial myofibroblasts that localize in the alveolar wall, derive from PDGFRβ pericytes, express NO-GC and produce collagen 1. (2) intra-alveolar myofibroblasts which do not derive from pericytes (but express PDGFRβ de novo after injury), are negative for NO-GC, have a large multipolar shape and appear to spread over several alveoli within the injured areas. Moreover, NO-GC expression is reduced during fibrosis, i.e., after pericyte-to-myofibroblast transition. In summary, αSMA/PDGFRβ-positive myofibroblasts should not be addressed as a homogeneous target cell type within pulmonary fibrosis.