Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue

Human
pluripotent stem cell-derived hepatocytes (hPSC-HEP) display
many properties of mature hepatocytes, including expression of important
genes of the drug metabolizing machinery, glycogen storage, and production
of multiple serum proteins. To this date, hPSC-HEP do not, however,
fully recapitulate the complete functionality of in vivo mature hepatocytes.
In this study, we applied versatile bioinformatic algorithms, including
functional annotation and pathway enrichment analyses, transcription
factor binding-site enrichment, and similarity and correlation analyses,
to datasets collected from different stages during hPSC-HEP differentiation
and compared these to developmental stages and tissues from fetal
and adult human liver. Our results demonstrate a high level of similarity
between the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis.
Importantly, the transcriptional correlation of hPSC-HEP with adult
liver (AL) tissues was higher than with fetal liver (FL) tissues (0.83
and 0.70, respectively). Functional data revealed mature features
of hPSC-HEP including cytochrome P450 enzymes activities and albumin
secretion. Moreover, hPSC-HEP showed expression of many genes involved
in drug absorption, distribution, metabolism, and excretion. Despite
the high similarities observed, we identified differences of specific
pathways and regulatory players by analyzing the gene expression between
hPSC-HEP and AL. These findings will aid future intervention and improvement
of in vitro hepatocyte differentiation protocol in order to generate
hepatocytes displaying the complete functionality of mature hepatocytes.
Finally, on the transcriptional level, our results show stronger correlation
and higher similarity of hPSC-HEP to AL than to FL. In addition, potential
targets for further functional improvement of hPSC-HEP were also identified.