ATSC transplantation contributes to liver regeneration following paracetamol-induced acute liver injury through differentiation into hepatic-like cells

ATSC 移植通过分化为肝样细胞促进对乙酰氨基酚诱发的急性肝损伤后的肝脏再生

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作者:Themistoklis Feretis, Charalampos Katselis, Ioannis G Papanikolaou, Konstantinos Apostolou, Spyridon Tsikalakis, Konstantinos G Toutouzas, George Theodoropoulos, Eleni Andrianna Trigka, Angelica A Saetta, Nicholas Alexakis, Manousos Konstandoulakis, Kalliopi Tsarea, Maria Karamperi, Dimitrios Kletsa

Conclusion

The study showed the positive effects of transplanted adipose tissue stem cells (ATSCs) on liver regeneration (LG) through hepatotrophic factors. Furthermore, increased expression of hepatic specific proteins was recorded in ATSC transplanted groups that indicate stem cells differentiation into hepatic cells.

Material and methods

ALI was induced in Wistar rats using paracetamol. ATSCs were transplanted via the intravenous, portal vein, or intrahepatic route directly onto the liver parenchyma. Histological evaluation was conducted to assess drug-induced injury following transplantation. Fluorescence in situ hybridization (FISH) was used to verify the location of stem cells on the liver parenchyma. The effect of those cells on liver regeneration was tested by immunohistochemistry for hepatic growth factor (HGF). In addition, reverse transcription-quantitative PCR (qRT-PCR) was used to assess hepatic growth factor (HGF), hepatic nuclear factor 4α (HNF4α), cytochrome P450 1A2 (CYP1A2) and α-fetoprotein (AFP) mRNA expression.

Methods

ALI was induced in Wistar rats using paracetamol. ATSCs were transplanted via the intravenous, portal vein, or intrahepatic route directly onto the liver parenchyma. Histological evaluation was conducted to assess drug-induced injury following transplantation. Fluorescence in situ hybridization (FISH) was used to verify the location of stem cells on the liver parenchyma. The effect of those cells on liver regeneration was tested by immunohistochemistry for hepatic growth factor (HGF). In addition, reverse transcription-quantitative PCR (qRT-PCR) was used to assess hepatic growth factor (HGF), hepatic nuclear factor 4α (HNF4α), cytochrome P450 1A2 (CYP1A2) and α-fetoprotein (AFP) mRNA expression.

Results

Immunohistochemical staining for HGF was stronger in the transplanted groups than that in the control group (P<0.001). HNF4α and HGF mRNA levels were increased on day 7 following transplantation (P<0.001 and P=0.009, respectively). CYP1A2 mRNA levels were also increased (P=0.013) in the intravenous groups, while AFP levels were higher in the intrahepatic groups (P=0.006). ATSC transplantation attenuates ALI injury and promotes liver regeneration. Furthermore, expression of specific hepatic enzymes points to ATSC hepatic differentiation.

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