Engraftment of Adult Human Lung Tissue in Nonobese Diabetic/Severe Combined Immunodeficient Mice: A Novel Lung Epithelial Regeneration Model

Abstract

Objectives: Injury causes the disruption of homeostatic cell-cell interactions and epithelial regeneration is part of the threshold response. Due to the lack of a good animal model for the investigation of these mechanisms, the kinetics of cell proliferation after injury to the human respiratory tract are poorly understood. Methods: To create a better model of human bronchioloalveolar epithelial regeneration, we engrafted adult human lung tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Then the lung tissue was studied at various times up to 20 weeks after implantation. Results: The xenografts of bronchiolar epithelium showed characteristic features, including positivity for specific human antigens, and extensive regeneration was observed within 8 weeks after implantation. In addition, a few alveolar type II epithelial cells expressing prosurfactant protein C were detected in some areas. The distal alveolar spaces were filled with protein-rich material and were markedly dilated. Abundantly ciliated secretory epithelium, which was similar to normal adult bronchiolar epithelium, was observed within 16 weeks after implantation in the mice. All of the human lung tissue specimens that were implanted subcutaneously into the backs of the mice developed well and remained viable for 20 weeks. Each type of adult human lung epithelial cell showed a different mode of proliferation. Bronchiolar epithelial cells proliferated earlier, with MIB-1 labeling of up to 20% of the cells in the grafts at 8 weeks, while alveolar type II cells proliferated later, with labeling of up to 5% of graft cells at 12 weeks. Conclusion: This model seems to allow adult human lung epithelial regeneration to be investigated in vivo over the long term.

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

“…Thus, the present studies corroborate and extend previous experimental findings that implicate the critical dependence of T-cell alloresponses in the development of OB. 16,[33][34][35] Although this human-murine chimeric system appears to have singular relevance for study of OB in lung transplantation recipients, the methodology has some potential limitations (as do most other animal models of human disease). Among other considerations, the apparent inability of this particular mouse strain to support engraftment and expansions of other relevant human immune effector cells (eg, B cells) seems to preclude study of contributions by these other, potentially important elements.…”