Sall4 Regulates Cell Fate Decision in Fetal Hepatic Stem/Progenitor Cells
| Autor: | Akihide Kamiya, Hisao Tajiri, Ryuichi Nishinakamura, Mikio Zeniya, Tsunekazu Oikawa, Sei Kakinuma, Hiromitsu Nakauchi |
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| Rok vydání: | 2009 |
| Předmět: |
Mice
Nude Biology Cell fate determination Mice SALL4 medicine Animals Cell Lineage Progenitor cell Embryonic Stem Cells Gene knockdown Hepatology Embryogenesis Age Factors Gastroenterology Gene Expression Regulation Developmental Cell Differentiation Embryonic stem cell Molecular biology eye diseases DNA-Binding Proteins Transplantation Liver Hepatocytes Hepatocyte growth factor Bile Ducts Biomarkers Stem Cell Transplantation Transcription Factors medicine.drug |
| Zdroj: | Gastroenterology. 136:1000-1011 |
| ISSN: | 0016-5085 |
| Popis: | Background & Aims Fetal hepatic stem/progenitor cells, called hepatoblasts , differentiate into both hepatocytes and cholangiocytes. The molecular mechanisms regulating this lineage segmentation process remain unknown. Sall4 has been shown to be among the regulators of organogenesis, embryogenesis, maintenance of pluripotency, and early embryonic cell fate decisions in embryonic stem cells. The expression and functional roles of Sall4 during liver development have not been elucidated. We here provide their first description in hepatoblasts. Methods To investigate functions of Sall4 in fetal liver development, Dlk + CD45 − Ter119 − hepatoblasts derived from embryonic day 14 mouse livers were purified, and in vitro gain and loss of function analyses and in vivo transplantation analyses were performed using retrovirus- or lentivirus-mediated gene transfer. Results We demonstrated that Sall4 was expressed in fetal hepatoblasts but not adult hepatocytes. The expression level of Sall4 gradually fell during liver development. Overexpression of Sall4 in hepatoblasts significantly inhibited maturation induced by oncostatin M and extracellular matrix in vitro, as evidenced by morphologic changes and suppression of hepatic maturation marker gene expression. When bile duct-like structures were induced by collagen gel-embedded culture, overexpression of Sall4 markedly augmented size and number of cytokeratin19 + -branching structures. Knockdown of Sall4 inhibited formation of these branching structures. With in vivo transplantation, Sall4 enhanced differentiation of cytokeratin19 + -bile ducts derived from transplanted hepatoblasts. Conclusions These results suggest that Sall4 plays a crucial role in controlling the lineage commitment of hepatoblasts not only inhibiting their differentiation into hepatocytes but also driving their differentiation toward cholangiocytes. |
| Databáze: | OpenAIRE |
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