Faculty Collaboration Database

Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Stem Cell Res 2012 Nov;9(3):196-207

Date

08/14/2012

Pubmed ID

22885101

Pubmed Central ID

PMC3619384

DOI

10.1016/j.scr.2012.06.004

Scopus ID

2-s2.0-84864564708 (requires institutional sign-in at Scopus site)   97 Citations

Abstract

UNLABELLED: Maturation of induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs) has been proposed to address the shortage of human hepatocytes for therapeutic applications. The purpose of this study was to evaluate hiPSCs, HLCs and hepatocytes, all of human origin, in terms of performance metrics of relevance to cell therapies. hiPSCs were differentiated to HLCs in vitro using an established four-stage approach. We observed that hiPSCs had low oxygen consumption and possessed small, immature mitochondria located around the nucleus. With maturation to HLCs, mitochondria showed characteristic changes in morphology, ultrastructure, and gene expression. These changes in mitochondria included elongated morphology, swollen cristae, dense matrices, cytoplasmic migration, increased expression of mitochondrial DNA transcription and replication-related genes, and increased oxygen consumption. Following differentiation, HLCs expressed characteristic hepatocyte proteins including albumin and hepatocyte nuclear factor 4-alpha, and intrinsic functions including cytochrome P450 metabolism. But HLCs also expressed high levels of alpha fetoprotein, suggesting a persistent immature phenotype or inability to turn off early stage genes. Furthermore, the levels of albumin production, urea production, cytochrome P450 activity, and mitochondrial function of HLCs were significantly lower than primary human hepatocytes.

CONCLUSION: - hiPSCs offer an unlimited source of human HLCs. However, reduced functionality of HLCs compared to primary human hepatocytes limits their usefulness in clinical practice. Novel techniques are needed to complete differentiation of hiPSCs to mature hepatocytes.

Author List

Yu Y, Liu H, Ikeda Y, Amiot BP, Rinaldo P, Duncan SA, Nyberg SL

MESH terms used to index this publication - Major topics in bold

Cell Differentiation
Cell- and Tissue-Based Therapy
Cells, Cultured
Cytochrome P-450 Enzyme System
Hepatocyte Nuclear Factor 4
Hepatocytes
Humans
Induced Pluripotent Stem Cells