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

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SARS-Cov-2 Infection and Disease Modelling Using Stem Cell Technology and Organoids International Journal of Molecular Sciences Review SARS-CoV-2 Infection and Disease Modelling Using Stem Cell Technology and Organoids Marta Trevisan , Silvia Riccetti, Alessandro Sinigaglia and Luisa Barzon * Department of Molecular Medicine, University of Padova, 35121 Padova, Italy; [email protected] (M.T.); [email protected] (S.R.); [email protected] (A.S.) * Correspondence: [email protected] 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 differenti- ated 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 Citation: Trevisan, M.; Riccetti, S.; poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms Sinigaglia, A.; Barzon, L. SARS-CoV-2 and vascular damage result from the indirect effects of systemic inflammatory and immunological Infection and Disease Modelling hyper-responses to SARS-CoV-2 infection. Using Stem Cell Technology and Organoids. Int. J. Mol. Sci. 2021, 22, Keywords: lung; airway epithelial cells; central nervous system; gastrointestinal tract; cardiovascular 2356. https://doi.org/10.3390/ system; SARS-CoV-2; ACE2; tropism; innate immune response; pathogenesis ijms22052356 Academic Editors: Manuel Scimeca, Orazio Schillaci, Alessandro Mauriello and Nicoletta Urbano 1. Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December Received: 12 January 2021 2019 in Wuhan, China, where clusters of cases of severe interstitial pneumonia were identi- Accepted: 23 February 2021 fied [1–6]. The virus has rapidly spread worldwide leading the World Health Organization Published: 26 February 2021 (WHO) to declare COVID-19 a pandemic threat in March 2020. One year after 31 December 2019, when the first infections were identified, 191 countries have reported COVID-19 cases, Publisher’s Note: MDPI stays neutral accounting for over 82 million cases and 1.8 million deaths worldwide [7]. with regard to jurisdictional claims in Like the other respiratory coronaviruses, SARS-CoV-2 is mainly transmitted by respi- published maps and institutional affil- ratory droplets, while the role of airborne and fecal–oral transmission and direct contact iations. with contaminated surfaces is uncertain [8,9]. Clinical presentation of the disease caused by SARS-CoV-2, named coronavirus disease 2019 (COVID-19) by WHO, ranges from a mild disease to a potentially fatal acute respiratory distress syndrome (Figure1). Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 2356. https://doi.org/10.3390/ijms22052356 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 2356 2 of 19 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 19 FigureFigure 1.1.Clinical Clinical presentationpresentation of of SARS-CoV-2 SARS-CoV-2 infection: infection: About About 20–40% 20–40% of of SARS-CoV-2 SARS-CoV-2 infections infections are asymptomatic,are asymptomatic, especially especially in young in young individuals individual [10s– [10–13].13]. Mild Mild symptoms symptoms are reportedare reported in about in about 80% 80% of symptomatic infections (with or without mild pneumonia), severe disease in about 15%, of symptomatic infections (with or without mild pneumonia), severe disease in about 15%, critical critical disease in 5% [14]. The risk of death from SARS-CoV-2 infection has been estimated as 0.3% disease in 5% [14]. The risk of death from SARS-CoV-2 infection has been estimated as 0.3% [15]. [15]. Elderly age, male gender, and presence of co-morbidities are risk factors for severe disease Elderly[16,17]. age, male gender, and presence of co-morbidities are risk factors for severe disease [16,17]. In addition, SARS-CoV-2 infection has been associated with a variety of clinical condi- In addition, SARS-CoV-2 infection has been associated with a variety of clinical con- tions, including a new multisystem inflammatory syndrome in older children, manifested ditions, including a new multisystem inflammatory syndrome in older children, mani- by severe abdominal pain, cardiac dysfunction and shock [18], pulmonary fibrosis, neuro- fested by severe abdominal pain, cardiac dysfunction and shock [18], pulmonary fibrosis, logical and neuropsychiatric complications (cerebrovascular events, encephalitis, Guillain neurological and neuropsychiatric complications (cerebrovascular events, encephalitis, Barré syndrome, altered mental status) [19], acute pancreatitis, coagulopathy, renal failure, Guillain Barré syndrome, altered mental status) [19], acute pancreatitis, coagulopathy, re- diabetes, and dermatological lesions [20,21]. nal failure, diabetes, and dermatological lesions [20,21]. Unprecedented research efforts have rapidly allowed the understanding of the epi- demiology,Unprecedented biology, and research pathogenesis efforts have of SARS-CoV-2 rapidly allowed infection the understanding and the development of the epi- or antiviraldemiology, therapies biology, and and prophylactic pathogenesis vaccines of SARS-CoV-2 [22–24]. Generation infection and of experimental the development models or ofantiviral SARS-CoV-2 therapies infection and prophylactic and disease vaccines has been [22–24]. crucial Generation to understand of experimental the biology models of the virus,of SARS-CoV-2 to dissect theinfection pathogenic and disease mechanisms has been of disease,crucial to and understand to develop the antiviral biology drugs. of the Whilevirus, animalto dissect models the pathogenic are still required mechanisms in preclinical of disease, studies and for to vaccine develop development antiviral drugs. [25], inWhile vitro animalmodels models established are still from required stem cellsin prec andlinical organoids studies are for increasingly vaccine development being used [25], as cruelty-freein vitro models and established valuable systems from stem for pathogenesis cells and organoids and drug are discovery increasingly studies being [26 used] and as providedcruelty-free a significant and valuable contribution systems for to pathogen the understandingesis and drug of SARS-CoV-2 discovery studies infection [26] andand COVID-19provided a pathogenesis significant contribution [27]. In this reviewto the articleunderstanding on the use of of SARS-CoV-2 stem cell technology infection andand organoidsCOVID-19 for pathogenesis COVID-19 [27]. modelling In this andreview drug article discovery, on the weuse highlight of stem cell the technology contributions and andorganoids the potentialities for COVID-19 of these modelling biotechnological and drug discovery, tools to the we advancement highlight the of contributions knowledge onand disease the potentialities pathogenesis. of these In addition, biotechnologica we contributel tools to a the brief advancement update on of the knowledge genetic and on biologicaldisease pathogenesis. features of SARS-CoV-2 In addition, andwe contribu on COVID-19te a brief pathogenesis. update on the genetic and biolog- ical features of SARS-CoV-2 and on COVID-19 pathogenesis. 2. Genetic and Biological Features of SARS-CoV-2 2. GeneticCoronaviruses and Biological are enveloped, Features single-stranded,of SARS-CoV-2 positive-sense RNA viruses that in- fect aCoronaviruses variety of vertebrate are enveloped, host species. single-stranded, Like the two positive-sense other highly RNA pathogenic viruses humanthat in- coronavirusesfect a variety of SARS-CoV vertebrate and host MERS-CoV, species. Like SARS-CoV-2 the two other is classifiedhighly pathogenic in the Betacoronavirus human coro- genusnaviruses of the SARS-CoVCoronaviridae and MERS-CoV,family, and, SARS-CoV-2 together with is SARS-CoV, classified in it the belongs Betacoronavirus to the Severe ge- acutenus of respiratory the Coronaviridae syndrome-related family, and, coronavirus togetherspecies with SARS-CoV, [28]. The virus it belongs shares to 79.6% the Severe sequence acute identityrespiratory with syndrome-related SARS-CoV, which coronavirus was responsible species [28]. for The outbreaks virus shares of severe79.6% sequence acute respira- iden- torytity with syndrome SARS-CoV, (SARS) which in Guangdong was responsible Province, for outbreaks China, 2002–2003 of severe [acute6], and respiratory 96% identity syn- withdrome other (SARS) SARS-like in Guangdong betacoronaviruses Province, China, of bat origin2002–2003
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