Human‐induced pluripotent stem cell‐derived hepatocyte platform in modeling of SARS‐CoV‐2 infection

Background and Aim Currently, SARS‐CoV‐2 is still spreading rapidly and globally. A large proportion of patients with COVID‐19 developed liver injuries. The human‐induced pluripotent stem cell (iPSC)‐derived hepatocytes recapitulate primary human hepatocytes and have been widely used in studies of liver diseases. Methods To explore the susceptibility of hepatocytes to SARS‐CoV‐2, we differentiated iPSCs to functional hepatocytes and tried infecting them with different MOI (1, 0.1, 0.01) of SARS‐CoV‐2. Results The iPSC‐derived hepatocytes are highly susceptible to virus infection, even at 0.01 MOI. Other than the ancestral strain, iHeps also support the replication of SARS‐CoV‐2 variants including alpha, beta, theta, and delta. More interestingly, the ACE2 expression significantly upregulated after infection, suggesting a vicious cycle between virus infection and liver injury. Conclusions The iPSC‐derived hepatocytes can support the replication of SARS‐CoV‐2, and this platform could be used to investigate the SARS‐CoV‐2 hepatotropism and hepatic pathogenic mechanisms. We differentiated iPSCs to functional hepatocytes (iHeps) and inoculated them with SARS‐CoV‐2 wild type. We then determine the viral load in supernatant and angiotensin‐converting enzyme 2 (ACE2) in cells, and found that the viral load was more than 1010 copies/mL and there was upregulation of ACE2 expression at 72 h after infection. We further investigated the susceptibility of iHeps to SARS‐CoV‐2 variants, and found that iHeps can also support the replication of Alpha, Beta, Theta and Delta variants vey well.