A Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma

TitleA Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma
Publication TypeJournal Article
Year of Publication2017
AuthorsHackett, TL, Ferrante, SC, Hoptay, CE, Engelhardt, JF, Ingram, JL, Zhang, Y, Alcala, SE, Shaheen, F, Matz, E, Pillai, DK, Freishtat, RJ
JournalThe American Journal of Respiratory Cell and Molecular Biology
Date Published03/2017
ISSNPrint: 1044-1549; Online: 1535-4989

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.