Journal article
A Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma
American journal of respiratory cell and molecular biology, Vol.56(3), pp.291-299
03/2017
DOI: 10.1165/rcmb.2016-0065MA
PMCID: PMC5359536
PMID: 27788019
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.
Details
- Title: Subtitle
- A Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma
- Creators
- Tillie-Louise Hackett - 1 Department of Anesthesiology, Pharmacology, and Therapeutics, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, CanadaSarah C Ferrante - 2 Department of Integrative Systems Biology andClaire E Hoptay - 3 Children's Research Institute: Center for Genetic Medicine ResearchJohn F Engelhardt - 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa; andJennifer L Ingram - 5 Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Health System, Durham, North CarolinaYulong Zhang - 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa; andSarah E Alcala - 3 Children's Research Institute: Center for Genetic Medicine ResearchFurquan Shaheen - 1 Department of Anesthesiology, Pharmacology, and Therapeutics, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, CanadaEthan Matz - 2 Department of Integrative Systems Biology andDinesh K Pillai - 6 Division of Pulmonary and Sleep Medicine, andRobert J Freishtat - 8 Division of Emergency Medicine, Children's National Health System, Washington, D.C
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.56(3), pp.291-299
- DOI
- 10.1165/rcmb.2016-0065MA
- PMID
- 27788019
- PMCID
- PMC5359536
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS R24 HL123482 / NHLBI NIH HHS UL1 TR000075 / NCATS NIH HHS R01 DK047967 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025369802771
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