Abstract
Hepatic stem/progenitor cells, hepatoblasts, have a high proliferative ability and can differentiate into mature hepatocytes and cholangiocytes. Therefore, these cells are considered to be useful for regenerative medicine and drug screening for liver diseases. However, it is problem that in vitro maturation of hepatoblasts is insufficient in the present culture system. In this study, a novel regulator to induce hepatic differentiation was identified and the molecular function of this factor was examined in embryonic day 13 hepatoblast culture with maturation factor, oncostatin M and extracellular matrices. Overexpression of the basic helix-loop-helix type transcription factor, Mist1, induced expression of mature hepatocytic markers such as carbamoyl-phosphate synthetase1 and several cytochrome P450 (CYP) genes in this culture system. In contrast, Mist1 suppressed expression of cholangiocytic markers such as Sox9, Sox17, Ck19, and Grhl2. CYP3A metabolic activity was significantly induced by Mist1 in this hepatoblast culture. In addition, Mist1 induced liver-enriched transcription factors, CCAAT/enhancer-binding protein α and Hepatocyte nuclear factor 1α, which are known to be involved in liver functions. These results suggest that Mist1 partially induces mature hepatocytic expression and function accompanied by the down-regulation of cholangiocytic markers.
Highlights
Hepatocytes are useful for drug metabolism and pharmacokinetic analyses[6]
To find the new transcriptional factor regulating liver maturation, we expressed these candidate genes in hepatic progenitor cells proliferating on laminin (HPPL), hepatic progenitor cell line[29], and checked expression of CYP3a11, the liver functional gene (Supplementary Fig. S1)
We found that the Basic helix-loop-helix (bHLH) type transcription factor Mist[1] could induce expression of CYP3a11 in HPPL
Summary
Hepatocytes are useful for drug metabolism and pharmacokinetic analyses[6]. A large number of hepatocytes are needed for these purposed; hepatocytes are not able to proliferate in vitro despite their high proliferation in vivo[7]. Previous studies have suggested that hepatocyte nuclear factors (HNFs) 1α , 1β , 3α , 3β , and γ , 4α , and 6 as well as the CCAAT/enhancer-binding protein (C/EBP) family (α , β , and γ ) are involved in acquiring hepatocyte functions in vivo[17,18]. Some of these transcription factors are used to differentiate pluripotent stem cells[19,20] and somatic cells[21,22,23] into hepatocyte-like cells. These data indicate that Mist[1] is a novel transcriptional factor that is involved in hepatoblast maturation
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