Human pluripotent stem cell-derived alveolar epithelial cells are alternatives for in vitro pulmotoxicity assessment

Abstract

Human pluripotent stem cell (hPSC)-derived alveolar epithelial cells (AECs) provide new opportunities for understanding lung development and the treatment of pulmonary diseases. However, toxicity assessments using hPSC-AECs have not been undertaken. In this study, we generated functional AECs from hPSCs and evaluated their inflammatory and apoptotic responses to cadmium (Cd) exposure (1, 5, and 10 μM) for 24 h compared with the human bronchial epithelial cell line (BEAS-2B) and primary AECs as controls. Our data showed that Cd (10 μM) treatment induced substantial inflammatory responses and apoptosis in BEAS-2B cells, but not in both hPSC-AECs and primary AECs. Interestingly, conditioned medium from AEC cultures significantly alleviated apoptotic and inflammatory responses to Cd exposure in BEAS-2B cells. Using cytokine arrays, several potential factors secreted from hPSC-AECs and primary AECs were detected and may be involved in reducing Cd-induced cytotoxicity. We also observed higher expression of surfactant proteins B and C in both hPSC-AECs and primary AECs, which may contribute to protection against Cd-induced cytotoxicity. These results suggested that hPSC-AECs phenotypically and functionally resemble primary AECs and could be more biologically relevant alternatives for evaluating the pathological contribution of confirmed or potential pulmotoxic materials included in smoking and microdust.

Diesel Particulate Matter 2.5 Induces Epithelial-to-Mesenchymal Transition and Upregulation of SARS-CoV-2 Receptor during Human Pluripotent Stem Cell-Derived Alveolar Organoid Development

“…Our system is based on optimized stepwise direct hPSC differentiation via mimicking of early alveolar developmental cues in a temporally controlled manner [ 25 ]. Furthermore, we have previously demonstrated that hPSC-derived AECs displayed similar phenotypes and cellular responses to cadmium exposure as those of hpAECs [ 26 ]. Using our efficient and reproducible protocols, we found that dPM2.5 exposure perturbed AEC differentiation and resulted in loss of epithelial features of hPSC-derived AECs and AOs, which was evidenced by upregulation of mesenchymal-related genes and EMT-mediated nuclear TFs.…”

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies

“…Our laboratory as well as others have successfully differentiated iPSCs to distal lung phenotypes that mimic type I and type II alveolar cells ( Mitchell et al, 2017 ; Wang et al, 2020 ; Alysandratos et al, 2020 preprint). Type I and type II alveolar cells are implicated in the functional regeneration of the distal lung after damage and are an excellent source for modeling hyperoxia-induced BPD ( Jacob et al, 2017 ; Heo et al, 2019 ). In addition to studying cell development using cell culture, explant lung culture is another option to investigate specific pathways and novel interactions affected by hyperoxic conditions.…”

Organoid Model in Idiopathic Pulmonary Fibrosis

“…Consequently, they showed that clinical viruses acquire genome-wide changes, leading to alterations in the viral surface glycoproteins, which is conductive for viral entry ( 15 ). Heo et al ( 16 ) have shown that hPSC-derived alveolar epithelial cells alleviated apoptotic and inflammatory responses against cadmium exposure. Recently, the established hPSC-derived epithelial cells are generated with alveolar epithelial organoids (AOs), and AOs treated with TGF-β1 exhibited collagen accumulation and fibrotic changes in the interstitial area of AOs ( Fig.…”