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Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl‐CoA desaturase 1 activity
Author(s) -
Rahimi Yaghoub,
Mehdizadeh Amir,
Nozad Charoudeh Hojjatollah,
Nouri Mohammad,
Valaei Kobra,
Fayezi Shabnam,
Darabi Masoud
Publication year - 2015
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/dgd.12255
Subject(s) - hepatocyte , cholesterol 7 alpha hydroxylase , cellular differentiation , hepatocyte nuclear factor 4 , chemistry , albumin , biology , stem cell , microbiology and biotechnology , biochemistry , bile acid , transcription factor , in vitro , gene , nuclear receptor
Stearoyl‐CoA desaturase 1 ( SCD 1) plays important roles in organ development, glucose tolerance, insulin sensitivity, and cancer. Here, we examined the role of SCD 1 for the differentiation of human induced pluripotent stem (hi PS ) cells to liver cells by using drug inhibition and biochemical experiments. hi PS cells cultured in a pro‐hepatic medium were exposed to an SCD 1 inhibitor at various stages throughout differentiation. Liver‐specific markers, specifically α‐fetoprotein, albumin and urea in conditioned medium, and hepatocyte nuclear factor 4 α ( HNF 4 α ) and cytochrome P450 7A1 ( CYP 7A1) gene expressions and triglyceride in cellular extracts were analyzed at various development stages. Measures of hepatocyte‐specific function and triglyceride accumulation in later stages were strongly inhibited a minimum of −29% ( P < 0.05) by SCD 1 inhibitor in the early stage of hepatic differentiation and effectively reversed (>30%, P < 0.01) by the addition of oleate. The results were also reproducible with human primary mononuclear cells ( hPMN ). SCD 1 inhibitor had no significant effect on liver‐specific markers when it was added in the hepatic maturation stage. However, it strikingly led to higher albumin (1.6‐fold, P = 0.03) and urea (1.9‐fold, P = 0.02) production, and HNF 4 α (1.9‐fold, P = 0.02) and CYP 7A1 (1.3‐fold, P = 0.03) expression upon incubation during the lineage‐commitment stage. Hepatic differentiation from cultured hi PS cells is sensitive to SCD 1 inhibition and this sensitivity is affected by the stage of cellular differentiation. Notably, findings also indicate that this notion can be extended to hPMN . The requirement for SCD 1 activity in functional differentiation of hepatocytes may have relevance for human liver disease and metabolic dysregulation.