title: A Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma.
abstract: Limited in vivo models exist to investigate the lung airway epithelial role in repair, regeneration, and pathology of chronic lung diseases. Herein, we introduce a novel animal model in asthma-a xenograft system integrating a differentiating human asthmatic airway epithelium with an actively remodeling rodent mesenchyme in an immunocompromised murine host. Human asthmatic and nonasthmatic airway epithelial cells were seeded into decellularized rat tracheas. Tracheas were ligated to a sterile cassette and implanted subcutaneously in the flanks of nude mice. Grafts were harvested at 2, 4, or 6 weeks for tissue histology, fibrillar collagen, and transforming growth factor-β activation analysis. We compared immunostaining in these xenografts to human lungs. Grafted epithelial cells generated a differentiated epithelium containing basal, ciliated, and mucus-expressing cells. By 4 weeks postengraftment, asthmatic epithelia showed decreased numbers of ciliated cells and decreased E-cadherin expression compared with nonasthmatic grafts, similar to human lungs. Grafts seeded with asthmatic epithelial cells had three times more fibrillar collagen and induction of transforming growth factor-β isoforms at 6 weeks postengraftment compared with nonasthmatic grafts. Asthmatic epithelium alone is sufficient to drive aberrant mesenchymal remodeling with fibrillar collagen deposition in asthmatic xenografts. Moreover, this xenograft system represents an advance over current asthma models in that it permits direct assessment of the epithelial-mesenchymal trophic unit.
authors: 1 Department of Anesthesiology, Pharmacology, and Therapeutics, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Tillie-Louise
authors: TL
authors: Hackett
authors: 2 Department of Integrative Systems Biology and.
authors: Sarah C
authors: SC
authors: Ferrante
authors: 3 Children's Research Institute: Center for Genetic Medicine Research.
authors: Claire E
authors: CE
authors: Hoptay
authors: 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa; and.
authors: John F
authors: JF
authors: Engelhardt
authors: 5 Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Health System, Durham, North Carolina.
authors: Jennifer L
authors: JL
authors: Ingram
authors: 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa; and.
authors: Yulong
authors: Y
authors: Zhang
authors: 3 Children's Research Institute: Center for Genetic Medicine Research.
authors: Sarah E
authors: SE
authors: Alcala
authors: 1 Department of Anesthesiology, Pharmacology, and Therapeutics, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Furquan
authors: F
authors: Shaheen
authors: 2 Department of Integrative Systems Biology and.
authors: Ethan
authors: E
authors: Matz
authors: 2 Department of Integrative Systems Biology and.|7 Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, D.C.|6 Division of Pulmonary and Sleep Medicine, and.
authors: Dinesh K
authors: DK
authors: Pillai
authors: 2 Department of Integrative Systems Biology and.|7 Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, D.C.|8 Division of Emergency Medicine, Children's National Health System, Washington, D.C.
authors: Robert J
authors: 0000-0002-7411-2342
authors: RJ
authors: Freishtat
mesh_terms: D000328:Adult; D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000473:pathology* / Q000503:physiopathology; D003710:Demography; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D064593:Heterografts / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000473:pathology*; D011916:Rats, Inbred F344; D015398:Signal Transduction; D014019:Tissue Donors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor
keywords: asthma; lung; remodeling