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

Artikel i vetenskaplig tidskrift
Författare Nidal Ghosheh
Barbara Küppers-Munther
Annika Asplund
Christian X Andersson
Petter Björquist
Tommy B Andersson
Helena Carén
Stina Simonsson
Peter Sartipy
Jane Synnergren
Publicerad i ACS omega
Volym 5
Nummer/häfte 10
Sidor 4816-4827
ISSN 2470-1343
Publiceringsår 2020
Publicerad vid Sahlgrenska Cancer Center
Institutionen för biomedicin, avdelningen för laboratoriemedicin
Sidor 4816-4827
Språk en
Länkar dx.doi.org/10.1021/acsomega.9b03514
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Cancer och onkologi, Medicinsk genetik

Sammanfattning

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.

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