title: Intercellular transfer of GPRC5B via exosomes drives HGF-mediated outward growth.
abstract: How cells communicate during development and regeneration is a critical question. One mechanism of intercellular communication is via exosomes, extracellular vesicles that originate by the fusion of multivesicular endosomes with the plasma membrane [1-8]. To model exosome-based intercellular communication, we used Madin-Darby canine kidney (MDCK) cell cysts grown in 3D gels of extracellular matrix, which form tubules in response to hepatocyte growth factor (HGF). We report that GPRC5B, an orphan G protein coupled receptor, is in exosomes produced by HGF-treated cysts and released into the cyst lumen. Exosomal GPRC5B is taken up by nearby cells and together with HGF promotes extracellular signal-regulated kinase 1/2 (ERK1/2) activation and tubulogenesis, even under conditions where tubulogenesis would otherwise not occur. Recovery from injury, such as acute kidney injury (AKI), often recapitulates developmental processes. Here, we show that GPRC5B is elevated in urinary exosomes from patients with AKI. Our results elucidate how GPRC5B is carried by exosomes and augments HGF-induced morphogenesis. The unexpected role of exosomes in transporting GPRC5B between cells during morphogenesis and the ability of GPRC5B to predict the disease state of AKI elucidate a novel mechanism for intercellular communication during development and repair.
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Medicine, Division of Nephrology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: keith.mostov@ucsf.edu.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D004285:Dogs; D055354:Exosomes / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: D043562:Receptors, G-Protein-Coupled; D017228:Hepatocyte Growth Factor