SARS-CoV-2 Infection and Disease Modelling Using Stem Cell Technology and Organoids

Abstract

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.

Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids

“…Human lung organoids (hLORGs) include cell types and structures that imitate bronchi/bronchioles surrounded by lung mesenchyme and cells, expressing alveolar-cell markers used for SARS-CoV-2 infection [ 17 ]. In fact, due to their physiological expression of both angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 (DPP-4) receptors, these cells are the best target for viral entry [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Moreover, hLORGs can be cultured in vitro for long periods (up to 85–100 days of cultures).…”

COVID-19 Neuropathology: evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei

“…In particular, it still remains to be elucidated whether neurological manifestations and neural damage are a direct consequence of viral invasion of the CNS, are due to post-infectious immune-mediated disease, or are the result of systemic disease 1, 6–11 . Studies on human neural cell cultures and brain organoids report conflicting data on SARS-CoV-2 neurotropism 12 . Overall, they suggest that SARS-CoV-2 does not infect and replicate efficiently in human neural cells, while it can replicate at high rates in choroid plexus epithelial cells 7, 13–14 .…”

Endothelial cell biomarkers in critically ill COVID‐19 patients with encephalitis

“…SARS‐CoV‐2 invades host cells through the angiotensin‐converting enzyme 2 receptor, neuropilin‐1, and CD147/Basigin, which are largely expressed in endothelial cells (Daly et al, 2020; Ferrario et al, 2005; Monteil et al, 2020a; Qanadli et al, 2020; Wang et al, 2020). Hence, there is direct evidence that SARS‐CoV‐2 can infect endothelial cells (Monteil et al, 2020b; Trevisan et al, 2021; Varga et al, 2020). SARS‐CoV‐2 elements were detected in endothelial cells of COVID‐19 patients, together with an accumulation of inflammatory cells and evidence of endothelial and inflammatory cell death (Varga et al, 2020).…”