Chimeric liver
Recent demonstrations that human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) can be differentiated into hepatocyte-like cells (HLCs) have potential to advance both regenerative medicine and hepatic disease research. For example, hepatitis C virus (HCV) infection produces a variety of clinical manifestations, ranging from short-term mild illness to serious chronic disease that results in liver failure; however, the lack of suitable models for this disease has hampered efforts to better understand HCV infection and evaluate potential therapies. Arnaud Carpentier and colleagues at the National Institutes of Health demonstrated that HLCs derived from either hESCs or hiPSCs can be engrafted into the livers of immunodeficient transgenic mice. HLCs were maintained within murine livers for at least 3 months and underwent further differentiation and proliferation. Cultured HLCs were permissible to HCV infection and generated an interferon response to the virus. Moreover, engrafted HLCs were readily infected with multiple HCV genotypes, and viral RNA was detected in sera of chimeric mice, but not controls. Together, the results from this study provide a system to further study HCV pathogenesis and potential therapeutic interventions. The accompanying image of a section of liver from an HLC-engrafted mouse demonstrates a lack of fusion between engrafted HLCs (red, human AAT) and murine hepatocytes (green, murine albumin). Nuclei stained blue with DAPI.
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Abstract
The demonstrated ability to differentiate both human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs) holds great promise for both regenerative medicine and liver disease research. Here, we determined that, despite an immature phenotype, differentiated HLCs are permissive to hepatitis C virus (HCV) infection and mount an interferon response to HCV infection in vitro. HLCs differentiated from hESCs and hiPSCs could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter. The HLCs were maintained for more than 3 months in the livers of chimeric mice, in which they underwent further maturation and proliferation. These engrafted and expanded human HLCs were permissive to in vivo infection with HCV-positive sera and supported long-term infection of multiple HCV genotypes. Our study demonstrates efficient engraftment and in vivo HCV infection of human stem cell–derived hepatocytes and provides a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection.
Authors
Arnaud Carpentier, Abeba Tesfaye, Virginia Chu, Ila Nimgaonkar, Fang Zhang, Seung Bum Lee, Snorri S. Thorgeirsson, Stephen M. Feinstone, T. Jake Liang
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)