A tissue-engineered model of fetal distal lung tissue

Abstract

In extending our previous studies toward development of an engineered distal lung tissue construct (M. J. Mondrinos, S. Koutzaki, E. Jiwanmall, M. Li, J. P. Dechadarevian, P. I. Lelkes, and C. M. Finck. Tissue Eng 12: 717-728, 2006), we studied the effects of exogenous fibroblast growth factors FGF10, FGF7, and FGF2 on mixed populations of embryonic day 17.5 murine fetal pulmonary cells cultured in three-dimensional collagen gels. The morphogenic effects of the FGFs alone and in various combinations were assessed by whole mount immunohistochemistry and confocal microscopy. FGF10/7 significantly increased epithelial budding and proliferation; however, only FGF10 alone induced widespread budding. FGF7 alone induced dilation of epithelial structures but not widespread budding. FGF2 alone had a similar dilation, but not budding, effect in epithelial structures, and, in addition, significantly enhanced endothelial tubular morphogenesis and network formation, as well as mesenchymal proliferation. The combination of FGF10/7/2 induced robust budding of epithelial structures and the formation of uniform endothelial networks in parallel. These data suggest that appropriate combinations of exogenous FGFs chosen to target specific FGF receptor isoforms will allow for control of lung epithelial and mesenchymal cell behavior in the context of an engineered system. We propose that tissue-engineered fetal distal lung constructs could provide a potential source of tissue or cells for lung augmentation in pediatric pulmonary pathologies, such as pulmonary hypoplasia and bronchopulmonary dysplasia. In addition, engineered systems will provide alternative in vitro venues for the study of lung developmental biology and pathobiology.