This project proposes to develop the methodologies necessary to derive a functioning transplantable humanized lung from normal or disease-specific induced pluripotent stem (iPS) cells. Successful transplantation of this bioengineered lung would imply that any patient with end-stage lung disease could receive an ex vivo bioengineered lung generated from autologous iPS cells obtained from a simple skin biopsy. Successful completion of this project would also result in the first three-dimensional model system able to examine human lung epithelial lineage relationships and able to functionally test putative human lung stem/progenitor populations both in vitro and in vivo. For this proposal we have assembled four teams with expertise in stem cell and developmental biology, tissue engineering, biomedical engineering, veterinary medicine, and lung cell biology. We propose to utilize iPS cells we have derived from humans with/without cystic fibrosis to develop methods for: a) directed differentiation of the iPS cells into lung epithelial progenitors and endothelial cells, b) ex vivo seeding of the resulting cells onto pulmonary airway, alveolar, and vascular compartments of decellularized human lung scaffolds, c) transplantation of the bioengineered lungs into large animal recipients, and d) development of an ex vivo 3D bioartificial lung model of inherited lung disease.
End stage lung diseases, such as cystic fibrosis and emphysema, are responsible for considerable morbidity and mortality. This transformative project proposes to develop the methodologies necessary to derive an entire functioning transplantable humanized lung from induced pluripotent stem (iPS) cells generated from skin biopsies of humans with cystic fibrosis. For pre-clinical testing the bioengineered humanized lungs, made by seeding the cells onto lung scaffolds, will be studied after transplantation into animals.
