The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation

Stem Cell Research & Therapy

Xiaoren Zhang¹  Yihua Huang²  Yingying Jing³  Jinghua Jiang⁴  Junxia Shi⁴  Changchun Shao⁴  Wenting Liu⁴  Xiaojuan Hou⁴  Rong Li⁴  Xue Yang⁴  Chen Zong⁴  Qiudong Zhao⁴  Lu Gao⁴  Lixin Wei⁴  Fei Ye⁴ 

[1] Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China;Department of Pathology, The School of Basic Medical Sciences, Fujian Medical University, 350108, Fuzhou, China;Institute of Translational Medicine, Shanghai University, 200444, Shanghai, China;Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 200438, Shanghai, China;

关键词: Lipopolysaccharide;    Toll-like receptor 4;    Hepatocytes;    Stemness maintenance;    Yes-associated protein 1;   

DOI  :  10.1186/s13287-021-02421-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

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