Human ES Cell-derived Hepatoblasts are an Optimal Lineage Stage for HCV Infection

Purpose: The hepatoblasts are found to be optimal stage, compared with hepatic stem cells (hHpSCs) and mature hepatocytes (hHeps). To identify the cellular determinants that correlated with HCV infection during hES cells’ differentiation, transcriptome profiling of cells at hHpSC, hHB, PreHep and hHep stages were compared with RNA sequencing.Results: In general, the gene expression profile of cells at each stage clustered closer to the HCV infected cells at the same stages. The genes involved in regulation of liver development were up-regulated along with processes of maturation. Among the genes positively related to HCV replication, ABCB6, CEBPD, TNFRSF10C, GTF3A, HAS1, UBE2J1 were highly expressed in mature hHeps, while IGFBP6, SMAD6, ITGA7 etc. were highly expressed in progenitor hHB stage. Most of the 66 genes reported to be involved in HCV assembly and secretion remained unchanged, except CX3CL1 and PROX1 increased in mature hepatocyte and ARHGAF increased in rogenitors. Families of viral restriction factors reported involved in HCV infection were significantly enriched in hHeps. Conclusions: HCV does not change the transcription profile of induced cells and use different genes to support HCV replication in the cells from different stage. Low level of expression of viral restriction factors makes hHBs an optimal host for HCV infection. Overall design: Examination of transcriptome profiles of each stage of hepatic lineage cells differentiated from hESCs; Examination of HCV associated host factors during hepatic differentiation. mRNA profiles of hHpSC, hHB, PreHep and hHep infected with or without HCV using Illumina GAIIx.