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

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.

Multiple relationships between aerosol and COVID-19: A framework for global studies

“…When PM 2.5 invades the human body, ACE-2, as the receptor for SARS-CoV-2 to enter cells, will protect against renin–angiotensin system-induced lung injuries by cleaving Angiotensin II to limit substrate availability in the adverse AEC-Ang II-Ang II receptor 1 axis ( Parajuli et al, 2014 ). Therefore, PM 2.5 can increase the SARS-CoV-2 susceptibility for human body by enhancing the expression of AEC-2 and its cofactor TMPRSS2 ( Kim et al, 2020 ). An in vivo experimental study has confirmed that the expression level of ACE-2 in the lung of experimental mice was significantly increased after being induced by PM 2.5 ( Lin et al, 2018 ).…”

The effect of environmental diesel exhaust pollution on SARS-CoV-2 infection: The mechanism of pulmonary ground glass opacity

“…Diesel fine PM (dPM) 2.5 exposure has been well documented to disturb alveolar epithelial cell differentiation, in parallel with the increased nicotinamide adenine dinucleotide phosphate oxidases expression, as well as inflammation. In response to the dPM2.5 exposure, ACE2 receptor via which SARS-CoV-2 enters the target cells, and the cofactor transmembrane protease serine 2 (TMPRSS2) are highly upregulated in the alveolar epithelial cells ( Kim et al, 2020a , 2020b ). Importantly, generation and emission of DEPs from diesel engines are one of the main components of aerial PM ( Ohtoshi et al, 1998 ).…”

“…1 B). Since the dimensions of SARS-CoV-2 varies between approximately 70–90 nm, it can be carried to many intracellular organelles after entrance to the human’s cells ( Kim et al, 2020a , 2020b ). Following the post-“Stay Home Order” period Northwestern US city, the median traffic intensity and road occupancy declined approximately by one-third to half.…”

On the importance of hygienic measures in the control of airborne infectious diseases

“…While public response to particulate matter toxicity, as an obscure risk that mainly has consequences in the long term, may be delayed for some time, recent research indicates that toxic particles in the atmosphere play an essential role in spreading the current COVID-19 pandemic, and that therefore their systematic removal is a high public health priority. Thus, for example, an undeniable and high correlation was found between the concentration of PM2.5 particles in the air, on one hand, and both incidence and mortality from COVID-19, on the other [12][13][14][15]. glo biti samo privremeno rešenje problema.…”

“…Iako se javno zdravstveni odgovor na toksičnost čestica, kao nejasan rizik koji uglavnom ima posledice u dužem vremenskom periodu, može odložiti na neko vreme, nedavna istraživanja pokazuju da toksične čestice u atmosferi igraju ključnu ulogu u širenju trenutne pandemije COVID-19 i da stoga njihovo sistematsko uklanjanje predstavlja cilj visokog prioriteta za javno zdravlje. Tako je, na primer, utvrđena nesporna i visoka korelacija između koncentracije čestica PM2,5 u vazduhu, s jedne strane, i incidencije i mortaliteta od COVID-19, s druge strane [12][13][14][15].…”