A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis
Ishikawa, G.; Peng, X.; McGovern, J.; Ghincea, A.; Woo, S.; Okuno, D.; Yu, S.; Lee, C. J.; Liu, A.; Saber, T.; Hu, B.; Sun, Y.; Sun, H.; Jumaily, K. A.; Feghali-Bostwick, C.; Sumida, T. S.; Sauler, M.; Ryu, C.; Herzog, E. L.
Show abstract
Fibrosis contributes to incurable pathologies in vital organs including the lung. Myofibroblasts are fibrogenic effector cells that accumulate via incompletely understood mechanisms. We discovered that 1-adrenoreceptor expressing myofibroblasts receive sympathetic nerve-derived noradrenergic inputs in fibrotic mouse and human lungs. We combined optical clearing, whole lung imaging, cell-specific gene deletion in sympathetic nerves and myofibroblasts, pharmacologic interventions, sympathetic nerve co-culture and precision-cut lung slices, with analysis of bronchoalveolar lavage fluid, lung tissues, single-cell RNA sequencing datasets, and isolated lung fibroblasts from patients with diverse forms of pulmonary fibrosis to characterize a fibrogenic unit comprised of aberrantly patterned sympathetic nerves and 1-adrenoreceptor subtype D expressing myofibroblasts. The discovery of this previously undefined nerve-fibroblast axis that is conserved across species demonstrates the pivotal contribution of nerves to tissue remodeling and heralds a novel paradigm in fibrosis research.
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