TY - JOUR T1 - Single-cell RNA-seq reveals spatially restricted multicellular fibrotic niches during lung fibrosis JF - bioRxiv DO - 10.1101/569855 SP - 569855 AU - Nikita Joshi AU - Satoshi Watanabe AU - Rohan Verma AU - Renea P. Jablonski AU - Ching-I Chen AU - Paul Cheresh AU - Paul A. Reyfman AU - Alexandra C. McQuattie-Pimentel AU - Lango Sichizya AU - Annette S. Flozak AU - Cara J. Gottardi AU - Carla M. Cuda AU - Harris Perlman AU - Manu Jain AU - David W. Kamp AU - GR Scott Budinger AU - Alexander V. Misharin Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/06/569855.abstract N2 - Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, spatial methods and single-cell RNA-seq to a spatially-restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that while tissue-resident interstitial macrophages, tissue-resident alveolar macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche, only monocyte-derived alveolar macrophages are causally related to fibrosis. Monocyte-derived alveolar macrophages were specifically localized to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including PDGFA. Moreover, we identified autocrine M-CSF/M-CSFR signaling in monocyte-derived alveolar macrophages as a novel mechanism promoting their self-maintenance and persistence in the fibrotic niche. Pharmacological blockade of M-CSF signaling led to disappearance of the established population of monocyte-derived alveolar macrophages. Thus, our data indicate that monocyte-derived alveolar macrophages are specifically recruited to the fibrotic niche where they are maintained by autocrine signaling and drive fibrosis by stimulating fibroblast proliferation. ER -