DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States
Paola Catanuto
DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States
Simone Pereira-simon
DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States
Xiaomei Xia
Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States
Shahriar Shahzeidi
Medical Director, Grand Health Institute, Miami, United States
Evan Roberts
Cancer Modeling Shared Resource Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States
John Ludlow
ZenBio Inc., Durham, United States
Suzana Hamdan
Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, United States; Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of Medicine, Miami, United States
Sylvia Daunert
Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, United States; Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of Medicine, Miami, United States; Miami Clinical and Translational Science Institute, University of Miami Miller School of Medicine, Miami, United States
Jennifer Parra
Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States
Rivka Stone
Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States
Irena Pastar
Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States
Marjana Tomic-Canic
Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States
Marilyn K Glassberg
DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States; Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States; Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Chicago, United States
Background: MicroRNAs (miRNA) and other components contained in extracellular vesicles may reflect the presence of a disease. Lung tissue, sputum, and sera of individuals with idiopathic pulmonary fibrosis (IPF) show alterations in miRNA expression. We designed this study to test whether urine and/or tissue derived exosomal miRNAs from individuals with IPF carry cargo that can promote fibrosis. Methods: Exosomes were isolated from urine (U-IPFexo), lung tissue myofibroblasts (MF-IPFexo), serum from individuals with IPF (n=16) and age/sex-matched controls without lung disease (n=10). We analyzed microRNA expression of isolated exosomes and their in vivo bio-distribution. We investigated the effect on ex vivo skin wound healing and in in vivo mouse lung models. Results: U-IPFexo or MF-IPFexo expressed miR-let-7d, miR-29a-5p, miR-181b-3p and miR-199a-3p consistent with previous reports of miRNA expression obtained from lung tissue/sera from patients with IPF. In vivo bio-distribution experiments detected bioluminescent exosomes in the lung of normal C57Bl6 mice within 5 min after intravenous infusion, followed by distribution to other organs irrespective of exosome source. Exosomes labeled with gold nanoparticles and imaged by transmission electron microscopy were visualized in alveolar epithelial type I and type II cells. Treatment of human and mouse lung punches obtained from control, non-fibrotic lungs with either U-IPFexo or MF-IPFexo produced a fibrotic phenotype. A fibrotic phenotype was also induced in a human ex vivo skin model and in in vivo lung models. Conclusions: Our results provide evidence of a systemic feature of IPF whereby exosomes contain pro-fibrotic miRNAs when obtained from a fibrotic source and interfere with response to tissue injury as measured in skin and lung models. Funding: This work was supported in part by Lester and Sue Smith Foundation and The Samrick Family Foundation and NIH grants R21 AG060338 (SE and MKG), U01 DK119085 (IP, RS, MTC).
