Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells.
Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells.
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DOI：
10.1016/j.ebiom.2018.08.014
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发表时间：
2018-09
期刊：
影响因子：
11.1
通讯作者：
Taniguchi H
中科院分区：
文献类型：
--
作者：
Nie YZ;Zheng YW;Miyakawa K;Murata S;Zhang RR;Sekine K;Ueno Y;Takebe T;Wakita T;Ryo A;Taniguchi H
近几十年来，针对B型肝炎病毒（HBV）的治疗方法得到了改善;然而，个体化治疗的发展受到缺乏个体化感染模型的限制。在这项研究中，我们使用人诱导多能干细胞（hiPSC）产生一个功能性肝类器官（LO），继承了供体的遗传背景，并评估其在模拟HBV感染和探索病毒-宿主相互作用中的应用。为了建立功能性hiPSC-LO，我们在三维微孔培养系统中用化学成分确定的培养基培养hiPSC衍生的内胚层、间充质和内皮细胞。基于细胞-细胞相互作用，这些细胞可以自我组织并逐渐分化成功能性类器官，其表现出比hiPSC衍生的肝样细胞（HLC）更强的肝功能。此外，功能性LO表现出比hiPSC-HLC更易受HBV感染，并且可以维持HBV增殖并长时间产生感染性病毒。此外，我们发现病毒感染可导致hiPSC-LO的肝功能障碍，肝脏基因表达下调，诱导释放早期急性肝衰竭标志物，并改变肝脏超微结构。因此，我们的研究表明，hiPSC-LO中的HBV感染可以重现病毒的生命周期和病毒引起的肝功能障碍，这表明hiPSC-LO可能为开发肝炎的个体化治疗提供有希望的个体化感染模型。
Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (LO) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus–host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC, and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis.
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影响因子：
56.3
作者：
Burgner, David;Jamieson, Sarra E.;Blackwell, Jenefer M.
通讯作者：
Blackwell, Jenefer M.
DOI：
10.1073/pnas.84.4.1005
发表时间：
1987-02-01
影响因子：
11.1
作者：
SELLS, MA;CHEN, ML;ACS, G
通讯作者：
ACS, G
影响因子：
50.3
作者：
Lau, Chi-Chiu;Sun, Tingting;Wong, Nathalie
通讯作者：
Wong, Nathalie
影响因子：
29.4
作者：
GALLE, PR;HAGELSTEIN, J;ZENTGRAF, H
通讯作者：
ZENTGRAF, H
影响因子：
--
作者：
Miyakawa K;Matsunaga S;Watashi K;Sugiyama M;Kimura H;Yamamoto N;Mizokami M;Wakita T;Ryo A
通讯作者：
Ryo A