Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells

Long-Term Chronic Toxicity Testing Using Human Pluripotent Stem Cell–Derived Hepatocytes

“…Protocols to differentiate human embryonic stem cells and human induced pluripotent stem cells into hepatocytes have improved immensely in recent years, and now hepatocyte cultures with high purity and many characteristics of functional hepatocytes can be obtained from hPSC (Brolen et al, 2010;Si-Tayeb et al, 2010;Touboul et al, 2010;Yildirimman et al, 2011;Hannan et al, 2013;Ulvestad et al, 2013;Szkolnicka et al, 2014). The fact that these cells can be derived in a robust and reproducible fashion from a well-characterized source makes them very attractive as a toxicity assessment model.…”

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

“…In addition, these cells can also be utilized for patient specific treatment (1,20). HPSCs have successfully been differentiated into hepatocytes (hPSC-HEP), sharing many features with in vivo hepatocytes, such as cytochrome P450 enzyme activity and glycogen storage, in addition to expression of several drug transporters (1,17,18,52,58). Furthermore, they are applicable for long-term toxicity studies (21) and can accurately classify toxic agents (55).…”

The importance of drug transporters in human pluripotent stem cells and in early tissue differentiation

“…Thus, characteristic transporter mRNA expression patterns for different cell types at various maturation stages can be investigated in an 165 isogenic system. [13,15] Findings of Rottenberg and colleagues [16,17] indicate that even a low-level increase in the mRNA levels of ABC transporters can be relevant and translate to transporter levels which are able to protect tumour cells against chemotherapy. In their 170 studies, drug-sensitive and drug-resistant tumour samples showed less than 10-fold difference for ABCB1 and less than 5-fold for ABCG2 mRNA levels.…”

“…In induced and directed hepatocyte, enterocyte or blood-brain epithelial 600 cell differentiation from embryonic stem cells, in addition to ABC transporters (see above), several SLC-type transporters are important developmental indicators. [1,15,[53][54][55][56][57][58][59][60] During stem cell differentiation into early kidney tissues, the expression patterns of the SLC12A1 (NA/K/Cl -thick 605 ascending limb the of Henle's loop), A3 (Na/Cl -distal convoluted tubule) and the SLC34A1 (Na/phosphate, proximal tubule) transporter proteins can be efficiently used as markers for kidney tubule development. [61] Similarly, specific substrate transporters in the SLC1 (PM glutamate, 610 aspartate or other neurotransmitter carriers), in the SLC6 (PM neurotransmitter and amino acid transporters) and in the SLC17 family (vesicular glutamate transporters) are recognized as regulated marker proteins, especially in neuronal differentiation.…”

“…[66] 640 The pattern of OATP expression (particularly SLCO1B1 and 1B3) has been already used to follow early hepatic, intestinal and blood-brain barrier epithelial cell differentiation from pluripotent stem cells. [15,67] While in foetal tissues, the OATP levels are low, fully differentiated hepato-645 cytes have high expression levels for selected OATPs, thus report the success of end-stage hepatocyte differentiation. [57] OATPs have also been used to characterize potential cancer stem cells.…”