Three-dimensional bioprinted hepatorganoids prolong survival of mice with liver failure.
Three-dimensional bioprinted hepatorganoids prolong survival of mice with liver failure.
复制标题
三维生物打印的肝类器官可延长肝衰竭小鼠的生存期
DOI：
10.1136/gutjnl-2019-319960
复制
发表时间：
2021-03
期刊：
影响因子：
24.5
通讯作者：
Mao Y
中科院分区：
文献类型：
--
作者：
Yang H;Sun L;Pang Y;Hu D;Xu H;Mao S;Peng W;Wang Y;Xu Y;Zheng YC;Du S;Zhao H;Chi T;Lu X;Sang X;Zhong S;Wang X;Zhang H;Huang P;Sun W;Mao Y
目的器官供体的短缺是终末期器官衰竭治疗的一个关键挑战，这促使了体外器官生成替代策略的发展。在这里，我们的目的是描述肝类器官，这是一种通过三维（3D）生物打印HepaRG细胞生成的肝脏组织模型，并研究其体外和体内的肝脏功能。根据特定的3D打印程序，使用HepaRG细胞和生物墨水构建3D生物打印的肝类器官（3DP-HO）。体外诱导分化7 d后检测3DP-HO的肝功能，并将其移植到Fah缺陷小鼠体内。通过小鼠的存活时间和肝损伤、人类肝功能标志物和人类特异性异喹代谢产物的产生来评估3DP-HO的体内肝功能。结果3DP-HO在分化7 d后获得了广泛的肝脏功能，如白蛋白分泌、药物代谢和糖原储存。移植到Fah-/-Rag 2-/-小鼠肝损伤模型的腹腔内后，3DP-HO进一步成熟并显示肝特异性蛋白的合成增加。特别地，小鼠获得了人类特异性药物代谢活性。移植的3DP-HO中还形成了功能性血管系统，进一步增强了3DP-HO的物质转运和肝脏功能。最重要的是，3DP-HO的移植显著提高了小鼠的存活率。结论3DP-HO肝组织模型具有在体肝脏功能，可减轻移植后的肝功能衰竭，提示3D生物打印技术可用于制备人肝组织，作为肝脏疾病治疗的替代移植供体。
Objective Shortage of organ donors, a critical challenge for treatment of end-stage organ failure, has motivated the development of alternative strategies to generate organs in vitro. Here, we aim to describe the hepatorganoids, which is a liver tissue model generated by three-dimensional (3D) bioprinting of HepaRG cells and investigate its liver functions in vitro and in vivo. Design 3D bioprinted hepatorganoids (3DP-HOs) were constructed using HepaRG cells and bioink, according to specific 3D printing procedures. Liver functions of 3DP-HOs were detected after 7 days of differentiation in vitro, which were later transplanted into Fah-deficient mice. The in vivo liver functions of 3DP-HOs were evaluated by survival time and liver damage of mice, human liver function markers and human-specific debrisoquine metabolite production. Results 3DP-HOs broadly acquired liver functions, such as ALBUMIN secretion, drug metabolism and glycogen storage after 7 days of differentiation. After transplantation into abdominal cavity of Fah-/-Rag2-/- mouse model of liver injury, 3DP-HOs further matured and displayed increased synthesis of liver-specific proteins. Particularly, the mice acquired human-specific drug metabolism activities. Functional vascular systems were also formed in transplanted 3DP-HOs, further enhancing the material transport and liver functions of 3DP-HOs. Most importantly, transplantation of 3DP-HOs significantly improved the survival of mice. Conclusions Our results demonstrated a comprehensive proof of principle, which indicated that 3DP-HO model of liver tissues possessed in vivo hepatic functions and alleviated liver failure after transplantation, suggesting that 3D bioprinting could be used to generate human liver tissues as the alternative transplantation donors for treatment of liver diseases.
登录
查看更多内容
人肝细胞来源的肝祖样细胞的扩增和分化及其在嗜肝病原体研究中的应用
影响因子：
44.1
作者：
Fu GB;Huang WJ;Zeng M;Zhou X;Wu HP;Liu CC;Wu H;Weng J;Zhang HD;Cai YC;Ashton C;Ding M;Tang D;Zhang BH;Gao Y;Yu WF;Zhai B;He ZY;Wang HY;Yan HX
通讯作者：
Yan HX
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.aav9750
发表时间：
2019-05-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Grigoryan B;Paulsen SJ;Corbett DC;Sazer DW;Fortin CL;Zaita AJ;Greenfield PT;Calafat NJ;Gounley JP;Ta AH;Johansson F;Randles A;Rosenkrantz JE;Louis-Rosenberg JD;Galie PA;Stevens KR;Miller JS
通讯作者：
Miller JS
影响因子：
1.7
作者：
Bianconi, Eva;Piovesan, Allison;Canaider, Silvia
通讯作者：
Canaider, Silvia
影响因子：
5.6
作者：
Hiller T;Berg J;Elomaa L;Röhrs V;Ullah I;Schaar K;Dietrich AC;Al-Zeer MA;Kurtz A;Hocke AC;Hippenstiel S;Fechner H;Weinhart M;Kurreck J
通讯作者：
Kurreck J