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Notch is the key factor in the process of fetal liver stem/progenitor cells differentiation into hepatocytes
Author(s) -
Wang Tao,
You Nan,
Tao Kaishan,
Wang Xing,
Zhao Ge,
Xia Ning,
Li Nanlin,
Tang Lijun,
Liu Weihui,
Dou Kefeng
Publication year - 2012
Publication title -
development, growth and differentiation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 66
eISSN - 1440-169X
pISSN - 0012-1592
DOI - 10.1111/j.1440-169x.2012.01363.x
Subject(s) - notch signaling pathway , progenitor cell , embryonic stem cell , biology , microbiology and biotechnology , stem cell , cellular differentiation , hepatocyte growth factor , hepatocyte , transplantation , immunology , receptor , medicine , signal transduction , genetics , in vitro , gene
Cell transplantation is efficient method to therapy end‐stage liver disease ( ESLD ). How to punctually induce stem cell differentiation into hepatocyte is still a challenge. Notch plays important roles in embryonic development and cell differentiation. However, during the differentiation process from fetal liver stem/progenitor cells ( FLSPC s) to mature hepatocytes, the contribution of Notch, especially which Notch receptor is primarily responsible, is unknown. First, specific Notch receptor responsible for FLSPC s differentiation was identified. On both tissue level and cell level, we found that Notch3 was the only receptor greater expressed in liver tissue at embryonic day ( ED ) 14 and FLSPC s, compared with the adult liver and BRL cells, respectively. Second, morphological phenotypic and functional aspects were analyzed to evaluate whether Notch inhibition by GSI s (γ‐secretase inhibitors, inhibitor of Notch) promotes the differentiation of FLSPC s into hepatocytes. Results showed that N ‐[ N ‐(3, 5‐Difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine t‐butyl ester ( DAPT ) as GSI s was able to induce FLSPC s differentiation into hepatocytes. The differentiated FLSPC s showed similar morphology to mature hepatocytes, expressed hepatic markers indicative of a mature developmental stage, and displayed similar functionality to mature hepatocytes. The differentiation efficiency by GSI s was similar to that by hepatocyte growth factor ( HGF ) induction. More specifically, as the differentiation of FLSPC s progressed towards hepatocytes, the expression of Notch3 was gradually down‐regulated, consistent with the down‐regulation of other stem cell markers. These findings imply that Notch3 may not only be a regulator of FLSPC s differentiation into hepatocytes, but also be a potential marker of FLSPC s.