Intra-tracheally injected human induced pluripotent stem cell-derived pneumocytes and endothelial cells engraft in the distal lung and ameliorate emphysema in a rat model.

OBJECTIVES: Pulmonary emphysema is characterized by the destruction of alveolar units and reduced gas exchange capacity. In the present study, we aimed to deliver induced pluripotent stem cell (iPSCs)-derived endothelial cells and pneumocytes to repair and regenerate distal lung tissue in an elastase-induced emphysema model.

METHODS: We induced emphysema in athymic rats via intratracheal injection of elastase as previously reported. At 21 and 35 days after elastase treatment, we suspended 80 million iPSCs-derived endothelial cells and 20 million iPSCs-derived pneumocytes in hydrogel and injected the mixture intra-tracheally. On day 49 after elastase treatment, we performed imaging, functional analysis, and collected lungs for histology.

RESULTS: Using immunofluorescence detection of human-specific HLA1, human-specific CD31, and anti-GFP for the reporter labeled pneumocytes, we found that transplanted cells engrafted in 14.69 ± 0.95% of the host alveoli and fully integrated to form vascularized alveoli together with host cells. Transmission electron microscopy confirmed the incorporation of the transplanted human cells and the formation of a blood-air barrier. Human endothelial cells formed perfused vasculature. Computed tomography scans revealed improved vascular density and decelerated emphysema progression in cell-treated lungs. Proliferation of both human and rat cell was higher in cell-treated vs non-treated controls. Cell treatment reduced alveolar enlargement, improved dynamic compliance and residual volume, and improved diffusion capacity.

CONCLUSIONS: Our findings suggest that human iPSC-derived distal lung cells can engraft in emphysematous lungs and participate in the formation of functional distal lung units to ameliorate the progression of emphysema.