Modulation of hepatitis B virus infection by epidermal growth factor secreted from liver sinusoidal endothelial cells
Modulation of hepatitis B virus infection by epidermal growth factor secreted from liver sinusoidal endothelial cells
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DOI：
10.1038/s41598-020-71453-5
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发表时间：
2020-09-01
影响因子：
4.6
通讯作者：
Kido, Taketomo
中科院分区：
文献类型：
--
作者：
Chen, Shin-Wei;Himeno, Misao;Kido, Taketomo
从人多能干细胞中提取的肝细胞可用于研究乙型肝炎病毒（HBV）感染，但感染效率较低。为了提高HBV感染ipsc源性肝细胞的效率，我们将肝细胞与肝非实质细胞共培养，发现肝窦内皮细胞（LSECs）通过分泌表皮生长因子（EGF）增强HBV感染。虽然EGF受体（EGFR）被认为是HBV的共同受体，但我们发现EGF在低剂量的EGF下增强HBV感染，而高剂量的EGF则抑制HBV感染。EGFR通过网格蛋白介导的内吞作用（CME）和网格蛋白独立的内吞作用（CIE）途径内化，这取决于EGF的剂量。在高剂量的EGF下，经CIE内吞的EGFR在溶酶体中被降解。这项研究首次提供证据，证明HBV在低剂量和高剂量EGF下分别通过CME和CIE途径被内吞。总之，我们利用ipsc衍生的肝细胞建立了一个体外HBV感染系统，并表明LSECs分泌的EGF以剂量依赖的方式调节HBV感染。
Hepatocytes derived from human iPSCs are useful to study hepatitis B virus (HBV) infection, however infection efficiency is rather poor. In order to improve the efficiency of HBV infection to iPSC-derived hepatocytes, we set a co-culture of hepatocytes with liver non-parenchymal cells and found that liver sinusoidal endothelial cells (LSECs) enhanced HBV infection by secreting epidermal growth factor (EGF). While EGF receptor (EGFR) is known as a co-receptor for HBV, we found that EGF enhanced HBV infection at a low dose of EGF, whereas EGF at a high dose suppressed HBV infection. EGFR is internalized by clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE) pathways depending on the dose of EGF. At a high dose of EGF, the endocytosed EGFR via CIE is degraded in the lysosome. This study is the first to provide evidence that HBV is endocytosed via CME and CIE pathways at a low and high dose of EGF, respectively. In conclusion, we developed an in vitro system of HBV infection using iPSC-derived liver cells, and show that EGF secreted from LSECs modulates HBV infection in a dose dependent manner.