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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

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      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.


      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.


      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.


      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.

      Graphical abstract

      Key words


      iPSCs (Induced pluripotent stem cells), hiPS (Human iPS), CT scan (Computed tomography scan), TEM (Transmission electron microscopy), TV (Tidal volume), PEEP (Positive end-expiratory pressure), PIP (Peak inspirational pressure), AT-1 (Pneumocytes type 1), AT-2 (Pneumocytes type 2), h-HLA1 (Human leukocyte antigen 1), NKX2.1-GFP (Ubiquitously expressed green fluorescent protein under the pneumocytes progenitor marker (NKX2.1 gene) promoter), SPC-TdTomato (Ubiquitously expressed TdTomato protein under the surfactant (SPC gene) promoter), Hu (Hounsfield units), MLI (Mean linear intercept), Cdyn (Dynamic compliance), RV (Residual Volume), RVOT (Ventricular outflow tract), BAL (Bronchioalveolar lavage), PCO2 (Carbon dioxide partial pressure), PO2 (Oxygen partial pressure), mmHg (Milimeter mercury (Pressure)), ml/cmH2O (Centimeter water (Dynamic compliance)), a-Cap (Aerocytes), g-Cap (General capillary cells), h-CD31 (Human specific CD31), CD144 (Vascular endothelium cadherin), UEA-1-positive (Ulex europaeus agglutinin-I labelled cells), EdU (5-ethynyl-2'-deoxyuridine), VEGF-165 (Vascular endothelial growth factor 165), SFM (Serum free medium), EGM2 (Endothelial growth medium-2), FGF-7 (Fibroblast growth factor 7), FGF-10 (Fibroblast growth factor 10), RNU (Athymic nude rats), 4%PFA (4% Paraformaldehyde), DMEM (Dulbecco's Modified Eagle Medium), DPBS (Dulbecco's phosphate-buffered saline), CO2 (Carbon dioxide), HEPES (N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid), DAPI (4′,6-diamidino-2-phenylindole), DAB (3, 3'-diaminobenzidine), Ctrl (Control), SE (Standard error), ANOVA (Analysis of variance)
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