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Abstract
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.
Graphical abstract
Graphical Abstract
Key words
Abbreviations:
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)To read this article in full you will need to make a payment
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Article info
Publication history
Accepted:
March 5,
2023
Received in revised form:
March 1,
2023
Received:
December 14,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Disclosure Statement: Dr. Harald Ott is the founder and CEO of IVIVA Medical
Funding Statement: This work was supported by a research grant by United Therapeutics Inc
Presentation: Presented at the AATS 102nd Annual Meeting, May 14-17, 2022, Boston, Massachusetts.
Central Picture Legend: Cell therapy ameliorates emphysema and improves vascularization.
Central Message
iPSCs derived endothelial cells and pneumocytes incorporate into host gas exchange tissue and improve emphysema progression and vascularization.
Perspective
The destruction of alveolar units and the resulting loss of diffusion capacity are the main features of emphysema. As a first step toward applying cellular therapy as a regenerative therapy we showed that iPSCs derived pneumocytes and endothelial cells can be delivered to the distal lung, engraft, and improve tissue structure and gas exchange function.
Identification
Copyright
© 2023 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
