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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

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  • Jung-Hyun Kim

    (Department of Internal Medicine, School of Medicine, Kangwon National University, 1 Kangwondaehakgil, Chuncheon 24341, Korea
    Environmental Health Center, Kangwon National University Hospital, Chuncheon 24341, Korea)

  • Jeeyoung Kim

    (Department of Internal Medicine, School of Medicine, Kangwon National University, 1 Kangwondaehakgil, Chuncheon 24341, Korea
    Environmental Health Center, Kangwon National University Hospital, Chuncheon 24341, Korea)

  • Woo Jin Kim

    (Department of Internal Medicine, School of Medicine, Kangwon National University, 1 Kangwondaehakgil, Chuncheon 24341, Korea
    Environmental Health Center, Kangwon National University Hospital, Chuncheon 24341, Korea)

  • Yung Hyun Choi

    (Department of Biochemistry, College of Korean Medicine, Dong-eui University, Busan 47227, Korea)

  • Se-Ran Yang

    (Department of Thoracic and Cardiology, School of Medicine, Kangwon National University, 1 Kangwondaehakgil, Chuncheon 24341, Korea)

  • Seok-Ho Hong

    (Department of Internal Medicine, School of Medicine, Kangwon National University, 1 Kangwondaehakgil, Chuncheon 24341, Korea
    Environmental Health Center, Kangwon National University Hospital, Chuncheon 24341, Korea)

Abstract

Growing evidence links prenatal exposure to particulate matter (PM2.5) with reduced lung function and incidence of pulmonary diseases in infancy and childhood. However, the underlying biological mechanisms of how prenatal PM2.5 exposure affects the lungs are incompletely understood, which explains the lack of an ideal in vitro lung development model. Human pluripotent stem cells (hPSCs) have been successfully employed for in vitro developmental toxicity evaluations due to their unique ability to differentiate into any type of cell in the body. In this study, we investigated the developmental toxicity of diesel fine PM (dPM2.5) exposure during hPSC-derived alveolar epithelial cell (AEC) differentiation and three-dimensional (3D) multicellular alveolar organoid (AO) development. We found that dPM2.5 (50 and 100 μg/mL) treatment disturbed the AEC differentiation, accompanied by upregulation of nicotinamide adenine dinucleotide phosphate oxidases and inflammation. Exposure to dPM2.5 also promoted epithelial-to-mesenchymal transition during AEC and AO development via activation of extracellular signal-regulated kinase signaling, while dPM2.5 had no effect on surfactant protein C expression in hPSC-derived AECs. Notably, we provided evidence, for the first time, that angiotensin-converting enzyme 2, a receptor to mediate the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) entry into target cells, and the cofactor transmembrane protease serine 2 were significantly upregulated in both hPSC-AECs and AOs treated with dPM2.5. In conclusion, we demonstrated the potential alveolar development toxicity and the increase of SARS-Cov-2 susceptibility of PM2.5. Our findings suggest that an hPSC-based 2D and 3D alveolar induction system could be a useful in vitro platform for evaluating the adverse effects of environmental toxins and for virus research.

Suggested Citation

  • Jung-Hyun Kim & Jeeyoung Kim & Woo Jin Kim & Yung Hyun Choi & Se-Ran Yang & Seok-Ho Hong, 2020. "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," IJERPH, MDPI, vol. 17(22), pages 1-15, November.
    • Handle: RePEc:gam:jijerp:v:17:y:2020:i:22:p:8410-:d:444695
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    1. Yumiko Imai & Keiji Kuba & Shuan Rao & Yi Huan & Feng Guo & Bin Guan & Peng Yang & Renu Sarao & Teiji Wada & Howard Leong-Poi & Michael A. Crackower & Akiyoshi Fukamizu & Chi-Chung Hui & Lutz Hein & S, 2005. "Angiotensin-converting enzyme 2 protects from severe acute lung failure," Nature, Nature, vol. 436(7047), pages 112-116, July.
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    Cited by:

    1. Alberto Izzotti & Paola Spatera & Zumama Khalid & Alessandra Pulliero, 2022. "Importance of Punctual Monitoring to Evaluate the Health Effects of Airborne Particulate Matter," IJERPH, MDPI, vol. 19(17), pages 1-18, August.

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