TY - JOUR
T1 - Hepatocyte-like cells differentiated from human induced pluripotent stem cells
T2 - Relevance to cellular therapies
AU - Yu, Yue
AU - Liu, Hongling
AU - Ikeda, Yasuhiro
AU - Amiot, Bruce P.
AU - Rinaldo, Piero
AU - Duncan, Stephen A.
AU - Nyberg, Scott L.
N1 - Funding Information:
This work was supported by grant(s) from the Optical Microscopy Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology ( NIH P30DK084567 ), Marriott Foundation , Wallace H. Coulter Foundation , Nature and Science Foundation of Jiangsu Province ( 10KJB320006 to Y. Yu ), the National Natural Science Foundation of China ( 81070361 to Y. Yu) and Jiangsu Province's Outstanding Medical Academic key program ( RC2011067 to Y. Yu).
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.scr.2012.06.004
DO - 10.1016/j.scr.2012.06.004
M3 - Review article
C2 - 22885101
AN - SCOPUS:84864564708
SN - 1873-5061
VL - 9
SP - 196
EP - 207
JO - Stem Cell Research
JF - Stem Cell Research
IS - 3
ER -