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

BACKGROUND: 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. METHODS: Using tamoxifen-inducible PDGFRβ-tdTomato mice (PDGFRβ-CreER(T2); 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. RESULTS: 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. CONCLUSION: In summary, αSMA/PDGFRβ-positive myofibroblasts should not be addressed as a homogeneous target cell type within pulmonary fibrosis.

• Aue, A.
• Englert, N.
• Harrer, L.
• Schwiering, F.
• Gaab, A.
• König, P.
• Adams, R.
• Schmidtko, A.
• Friebe, A.
• Groneberg, D.