Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids
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Protein & Cell
LETTER
Dear Editor, The emerging pandemic of coronavirus, SARS-CoV-2 (previously named 2019-nCoV), has posed significant threats to global public health (Wu et al., 2020). The dominant symptoms of coronavirus disease 2019 (COVID-19) are fever and cough (Chen et al., 2020; Huang et al., 2020). However, a proportion of patients showed multi-organ damage and dysfunction (Chen et al., 2020; Huang et al., 2020; Zhu et al., 2020). Of note, liver damage is emerging as a co-existed symptom reported in patients with COVID-19. A recent epidemiologic study in Shanghai (China) reported that 75 out of 148 (50.7%) COVID-19 patients had liver function abnormality, indicated by key liver function parameters above the normal range, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) or total bilirubin (TBIL) (Fan et al., 2020). A nationwide clinical study collecting 1,099 COVID-19 patients revealed that around 20% of patients had elevated ALT and AST and around 10% of patients had elevated TBIL. Especially, the percentage of patients with liver damage is much higher among severe COVID-19 patients than patients with mild symptoms (Huang et al., 2020). Although clinical correlation has been implicated, it remains unclear whether the liver damage is caused by direct virus infection in the liver or by systematic dysfunction such as cytokine storm. Viruses bind to host receptors to initiate infection. Recent studies have demonstrated that SARS-CoV-2 uses the SARS-CoV receptor angiotensin I converting enzyme 2 (ACE2) for host cell entering and transmembrane serine protease 2 (TMPRSS2) for viral spike (S) protein priming (Kuhn et al., 2004; Hoffmann et al., 2020; Wan et al., 2020; Zhu et al., 2020). It has been shown that ACE2 expression is widely distributed across human tissues, including lung, liver, kidney and multiple digestive tract organs (Qi et al., 2020; Zhang et al., 2020; Zhao et al., 2020). Significant enrichment of ACE2+ population in cholangiocytes compared to hepatocytes in the human healthy liver was reported recently (Chai et al., 2020), implying that SARS-CoV-2 might directly target ACE2+ cholangiocytes in patients. However, whether
© The Author(s) 2020
the virus indeed infects human cholangiocytes thus causes local damage has not been addressed yet. At present, due to the lack of suitable research models, the mode of virus transmission and tissue tropism is not well established yet. Studies on mechanisms of SARS-CoV-2 pathogenesis mainly depend on bioinformatics analysis, clinical characteristics and rare autopsy reports (Xu et al., 2020). Here we report the use of human organoids as a tool to investigate the SARS-CoV-2 infection and virus-induced tissue damage ex vivo at the cellular and molecular levels. In a three-dimensional (3D) culture system with defined culture medium, liver bile duct-derived progenitor cells embedded in Matrigel can self-assemble into long-term expandable 3D structures that termed “liver ductal organoids”, which retain their tis
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