The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation.
The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation.
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高水平脂多糖通过 YAP1 激活维持肝细胞的干性
DOI：
10.1186/s13287-021-02421-7
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发表时间：
2021-06-10
影响因子：
7.5
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Shao C;Yang X;Jing Y;Hou X;Huang Y;Zong C;Gao L;Liu W;Jiang J;Ye F;Shi J;Zhao Q;Li R;Zhang X;Wei L
肝脏具有强大的再生能力，这与门静脉（PV）中肝细胞的干性有关。然而，维持肝细胞干性的机制尚未阐明。在这里，我们假设来自门静脉的高水平脂多糖可能维持PV区肝细胞的干性。方法首先观察肝干细胞在门静脉和下腔静脉的位置和脂多糖（LPS）浓度。然后，我们通过使用抗生素消除LPS并敲除LPS受体TLR4来评估LPS对小鼠干性维持的影响。在体外，通过集落和球形成实验以及多能性和干细胞标志物表达的评估来研究LPS对肝细胞干性的影响。此外，我们还研究了LPS调控肝细胞干性的机制。最后，我们结扎门静脉分支进一步验证LPS的作用。结果我们发现，来自门静脉的高水平LPS与肝干细胞在PV区的位置相关，抗生素消除LPS可抑制干性标志物的表达。LPS促进AML12细胞集落和球的形成，诱导多能性和干细胞标记上调。此外，在重编程培养基中，LPS促进了成熟肝细胞向肝祖样细胞的去分化，在体内和体外均表现出双能分化能力。从机制上讲，LPS结合TLR4通过激活YAP1信号来调节肝细胞的干性，而YAP1的阻断则消除了LPS诱导的细胞干性和多能性标志物的上调。结论本研究提示LPS/TLR4/YAP1信号通路与肝细胞的干细胞性存在相关性，LPS参与肝细胞PV区干细胞性的维持。LPS可诱导成熟肝细胞脱分化为祖细胞样细胞，用于肝损伤修复。
BackgroundThe liver possesses a powerful regeneration ability, which is correlated with the stemness of hepatocytes in the portal vein (PV). However, the mechanism underlying the maintenance of hepatocyte stemness has not been elucidated. Here, we hypothesized that high levels of lipopolysaccharide from the portal vein might maintain the stemness of hepatocytes in the PV area.MethodsFirst, we examined the location of hepatic stem cells and the concentration of lipopolysaccharide (LPS) in the portal vein and inferior vena cava. Then, we assessed the effect of LPS on stemness maintenance in mice by using antibiotics to eliminate LPS and knocking out the LPS receptor,TLR4. In vitro, the effect of LPS on the stemness of hepatocytes was investigated by colony and sphere formation assays and assessment of pluripotent and stem cell marker expression. Furthermore, we studied the mechanism by which LPS regulates the stemness of hepatocytes. Finally, we ligated the portal vein branch to further verify the effect of LPS.ResultsWe found that a high level of LPS from the portal vein was correlated with the location of hepatic stem cells in the PV area, and elimination of LPS by antibiotics inhibited the expression of the stemness marker. LPS promoted colony and sphere formation and induced the upregulation of pluripotent and stem cell markers in AML12 cells. Furthermore, in the reprogramming medium, LPS facilitated the dedifferentiation of mature hepatocytes into hepatic progenitor-like cells, which exhibited a bipotent differentiation capacity in vivo and in vitro. Mechanistically, LPS bound TLR4 to regulate stemness of hepatocytes via the activation of YAP1 signaling, and blockade of YAP1 abolished the LPS-induced cell stemness and upregulation of pluripotent markers.ConclusionsOur study implies a correlation between LPS/TLR4/YAP1 signaling and cell stemness, and LPS was shown to be involved in stemness maintenance of hepatocytes in the PV area. LPS might be used to induce the dedifferentiation of mature hepatocytes into progenitor-like cells for repair of liver injury.
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影响因子：
4.8
作者：
Honda, Arata;Hirose, Michiko;Ogura, Atsuo
通讯作者：
Ogura, Atsuo
影响因子：
5.6
作者：
Kukolj, Tamara;Trivanovic, Drenka;Bugarski, Diana
通讯作者：
Bugarski, Diana
影响因子：
--
作者：
Abu Rmilah, Anan;Zhou, Wei;Nyberg, Scott L.
通讯作者：
Nyberg, Scott L.
影响因子：
3.1
作者：
Liu, SB;Gallo, DJ;Billiar, TR
通讯作者：
Billiar, TR
影响因子：
--
作者：
CORNELL, RP
通讯作者：
CORNELL, RP