Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice
Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice
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DOI：
10.1016/j.scr.2021.102425
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发表时间：
2021-06-10
影响因子：
1.2
通讯作者：
Sakai，Yoshio
中科院分区：
文献类型：
--
作者：
Ishida，Kosuke;Seki，Akihiro;Sakai，Yoshio
脂肪组织源性干细胞（ADSCs）被认为是治疗非酒精性脂肪性肝炎（NASH）的一种新方法；然而，其治疗作用的机制仍然知之甚少。在这项研究中，我们旨在研究Notch信号的关联，Notch信号在adsc介导的NASH治疗中对细胞增殖和分化至关重要。流式细胞术分析显示，ADSCs表达Notch配体JAG1、DLL1和DLL4。与Notch信号通路相关的基因在NASH模型小鼠肝细胞中的表达减弱。我们进一步观察到adsc介导的Notch信号的激活，以及增殖细胞核抗原+细胞的增加和tdt介导的dutp -生物素缺口末端标记+凋亡细胞的减少。棕榈酸诱导的脂肪变性肝细胞与ADSCs共培养可激活Notch信号通路，减少脂肪变性肝细胞的凋亡。此外，γ-分泌酶抑制剂抑制Notch信号和siRNA敲低Notch配体可减弱体外共培养ADSCsin的抗凋亡作用。我们的研究结果表明，Notch信号通路参与了ADSC治疗后NASH小鼠肝细胞凋亡的抑制和细胞增殖的恢复。
Adipose tissue-derived stem cells (ADSCs) have been suggested as a novel treatment for non-alcoholic steatohepatitis (NASH); however, the mechanisms underlying their therapeutic effect remain poorly understood. In this study, we aimed to investigate the association of Notch signaling, which is crucial for cellular proliferation and differentiation in ADSC-mediated treatment of NASH. Flow cytometry analysis of ADSCs showed that they expressed the Notch ligands JAG1, DLL1, and DLL4. The expression of genes associated with the Notch signaling pathway was attenuated in hepatocytes of NASH model mice. We further observed ADSC-mediated activation of Notch signaling in these hepatocytes in addition to an increase in proliferating cell nuclear antigen+cells and a decrease in TdT-mediated dUTP-biotin nick end labeling+apoptotic cells. Co-culture of palmitic acid-induced steatotic hepatocytes and ADSCs resulted in the activation of Notch signaling and reduction of apoptosis of steatotic hepatocytes. Moreover, inhibition of Notch signaling by a γ-secretase inhibitor and knockdown of Notch ligands using siRNA attenuated the anti-apoptotic effect of co-cultured ADSCsin vitro. Our findings show that the Notch signaling pathway is involved in the inhibition of apoptosis and restoration of cellular proliferation of hepatocytes from NASH mice following ADSC treatment.