The novel 2019 coronavirus infection (COVID-19), caused by severe respiratory coronavirus syndrome 2 (SARS-CoV-2), has captured more than 104 million lives and killed more than 2.3 million worldwide. Although mostly considered a respiratory disease, a quarter of COVID-19 patients also show other symptoms, often related to the gastrointestinal or nervous systems.
Many other cells in the body in addition to lung alveolar epithelial cells express angiotensin-converting enzyme 2 (ACE2) receptors – the channels through which the virus enters host cells. The heart, pancreas, GI tract, kidney, testis and other organs that express ACE2 receptors, and studies have shown that the virus affects the heart, vascular endothelial cells, kidney, liver and the pancreas.
In some cases, COVID-19 patients present with acute pancreatitis – a condition in which inflammation of the pancreas causes abdominal pain. Acute pancreatitis is also one of the most common hospitalized gastrointestinal causes in the US. At present, there is no knowledge of how SARS-CoV-2 affects the pancreas and what its effect is.
To understand how SARS-CoV-2 affects the pancreas and study its effects, a team of researchers used pancreatic cultures inserted into human iPSC (pluripotent stem cells). ) and analyzed the post-infection cellular and molecular changes.
The interdisciplinary team from Cedars-Sinai Medical Center, and the University of California, Los Angeles in the USA report on their views on the preprint server, medRxiv *. They confirm for the first time that SARS-CoV-2 can directly infect the pancreatic cells emanating from iPSC, with supporting evidence of the presence of the virus in the post-mortem print of human COVID cases. -19 confirmed.
They found that SARS-CoV-2 infection of iPSC-derived pancreatic cells induced an inflammatory inflammatory cytokine major, CXCL12. It is known to be involved in pancreatic dysfunction. They found that the SARS-CoV-2 overexpressed the ribosomal apparatus in the pancreatic cells and also increased the expression of some pancreatic ductal pressure response genes. Notably, the CXCL12, NFKB1, and STAT3 genes showed a significant increase compared to the control.
The researchers report that the transcriptional analysis of pancreatic cultures derived from iPSC SARS-CoV-2 revealed active viral replication and signatures of pancreatic-specific COVID-19 associated disease. The SRP protein targeting processes were regulated, indicating that host cell machinery was reproduced for viral replication.
For this study, established cell lines do not represent the pathophysiology of the human pancreas. Because the human pancreatic stem cells are largely accessible, the researchers developed innovative methods to generate pancreatic promoters from human pluripotent gas cells (iPSCs), which can differentiate into endocrine cells (β islet). ) and exocrine (acinar and ductal).
The researchers created the highly stable iPSCs from healthy volunteers at the iPSC Core at Cedars-Sinai Medical Center from the peripheral blood mononuclear cells (PMBCs) using oriP / EBNA1-based noninvasive episomal plasmid vectors . These human iPSCs were differentiated into adherent pancreatic (2D) and organoid (3D) cultures.
These cultures include cells representing the human endocrine pancreas expressing endocrine NKX6.1 and C-peptide, acocar exocrine Amylase and Chymotrypsin (CTRC) and exocrine ductal cells Cytokeratin19 (CK19) and SOX9, the researchers write.
From RNA order studies, they established that the pancreas, specifically the exocrine region (acinar and ductal cells), has a high sensitivity of ACE2. Gender and age show no difference in the expression of ACE2 receptors. The researchers showed that the pancreatic cells derived from iPSC used in this study exhibited ACE2 and TMPRSS2 expression. Both receptors are present in the pancreas, especially in the exocrine tract.
Expression of ACE2 and TMPRSS2 in exocrine pancreatic cells. A. iPanEXO CK19 ductal cells (red) displaying ACE2 expression (green). B. iPinEXO Acinar Cells Amylase (red), MIST1 (gray) exhibit ACE2 expression (green). C. iPanEXO Acinar and iPanENDO cultures contain some endocrine C-peptide cells, which also synergize with ACE2. D. Pancreatic exocrine cells derived from iPSC as well as human acinar glands and human ductal cell line H6C7 express ACE2 and TMPRSS2. Data are shown as mean ± SEM with statistical significance confirmed by unrepaired two-tailed test. * p <0.05, ** p <0.01, *** p <0.001, **** p <0.0001. A scale bar represents 100 μm, and 20 μm for extended panels next to main images.
In the context of the endocrine pancreas, patients with type I and type II diabetes have been shown to be at higher risk for COVID-19-related mortality. Diabetic COVID-19 patients, with associated comorbidities such as cardiovascular disease and renal impairment, respond to the severity of the disease. It is therefore important to know the mechanism of SARS-CoV-2 infection on human and exocrine endocrine pancreas.
The researchers show that the pancreatic cells including the endocrine and exocrine (acinar, and ductal) cell types are susceptible to SARS-CoV-2 infection, leading to morphological abnormalities as well as poor interpretation of key indicators.
The researchers have demonstrated for the first time that SARS-CoV-2 can infect infectious pancreatic cells derived from human iPSC. They support this with evidence that the virus is present in a post-mortem pancreatic print of COVID-19 confirmed human cases. Corresponding to the disease, the study shows significant inflammatory signatures.
The iPSC-based model described here provides a valuable novel platform for understanding pancreatic specific cellular responses to SARS-CoV-2 as well as for the development of antiviral drugs against SARS -CoV-2. ”
This study introduces a new model of pancreatic cultures derived from iPSC as a new pathway for understanding the SARS-CoV-2 disease. It may establish an excellent platform for screening specific antiviral drugs with endocrine and exocrine pancreas, the researchers write.
* Important message
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or treated as fixed information.