Abstract
Numb is a negative regulator of Notch signal pathway. Previous study has demonstrated that Notch signal pathway activation is required for hepatic progenitor cell (HPC) differentiating into cholangiocytes in cholestatic liver fibrosis (CLF), and Huang Qi Decoction (HQD) could prevent CLF through inhibition of the Notch signal pathway. However, the role of Numb in HQD against CLF is yet unclear. Thus, CLF rats transplanted into rat bone marrow-derived mesenchymal stem cells with knocked down Numb gene (BMSCNumb-KD) were treated with HQD. Simultaneously, Numb gene knockdown was also performed in WB-F344 cell line and then treated with refined HQD in vitro. In vivo study revealed that liver fibrosis was inhibited by HQD plus BMSCNumb-KD treatment, while Hyp content in liver tissue, the gene and protein expression of α-SMA, gene expression of Col I, TNF-α, and TGF-β1 were increased compared to that in HQD group. Furthermore, Notch signal pathway was inhibited by HQD plus BMSCNumb-KD, while the protein expression of Numb was decreased and RBP-Jκ and Hes1 was increased compared to that in HQD group. In vitro, HQD reduced the differentiation of WB-F344 cells into cholangiocyte phenotype, while this effect was attenuated after Numb-knockdown. This study highlights that the absence of hepatic stem cell Numb gene decreases effect of HQD against CLF, which give rise the conclusion that Numb might be a potential target for HQD against CLF.
Highlights
Human cholestatic liver disease is characterized by the progressive destruction of biliary epithelial cells (BECs), followed by fibrosis, cirrhosis and liver failure[1,2]
Our previous study showed that hepatic progenitor cells (HPCs) are the main source of BECs in cholestatic liver fibrosis (CLF) rat induced by bile duct ligation (BDL), and Notch signaling activation was found to be required for this pathological p rocess[12], suggesting that inhibition of Notch signal pathway might be of profound significance for treatment of CLF
The results showed that Notch-2/-3, DLL1, and Jag-1/-2 mRNA expression levels were significantly increased in the BDL group compared to that in the Sham group (P < 0.01), while Notch-2/-3 and Jag-1/-2 were significantly decreased in the Huang Qi Decoction (HQD) group compared to that in the BDL group (P < 0.05 or P < 0.01)
Summary
Human cholestatic liver disease is characterized by the progressive destruction of biliary epithelial cells (BECs), followed by fibrosis, cirrhosis and liver failure[1,2]. The inhibition of abnormal BEC activation and proliferation may partially or completely reverse cholestatic liver fibrosis (CLF)[3]. Our previous study showed that hepatic progenitor cells (HPCs) are the main source of BECs in CLF rat induced by bile duct ligation (BDL), and Notch signaling activation was found to be required for this pathological p rocess[12], suggesting that inhibition of Notch signal pathway might be of profound significance for treatment of CLF. Our previous study showed that HQD can inhibit the progression of CLF through inhibiting the Notch signal pathway and promoting the expressions of Numb mRNA and protein in hepatic progenitor c ells[14]. CLF rat transplanted into rat bone marrow-derived mesenchymal stem cells with Numb knockdown (BMSCNumb-KD) were found to promote CLF progression and reduced the effect of HQD against CLF
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