Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Division for Advanced Medical Sciences, National Center for Child Health and Development, Tokyo, Japan.
Cell Transplant. 2020 Jan-Dec;29:963689720964384. doi: 10.1177/0963689720964384.
Transplantation of liver organoids has been investigated as a treatment alternative to liver transplantation for chronic liver disease. Transportal approach can be considered as a method of delivering organoids to the liver. It is important to set the allowable organoid amount and verify translocation by intraportal transplantation. We first examined the transplantation tolerance and translocation of porcine fetal liver-derived allogeneic organoids using piglets. Fetal liver-derived organoids generated from the Kusabira Orange-transduced pig were transplanted to the 10-day-old piglet liver through the left branch of the portal vein. All recipients survived without any observable adverse events. In contrast, both local and main portal pressures increased transiently during transplantation. In necropsy samples, Kusabira Orange-positive donor cells were detected primarily in the target lobe of the liver and partly in other areas, including the lungs and brain. As we confirmed the transplantation allowance by porcine fetal liver-derived organoids, we performed intraportal transplantation of human-induced pluripotent stem cell (iPSC)-derived liver organoid, which we plan to use in clinical trials, and portal pressure and translocation were investigated. Human iPSC-derived liver organoids were transplanted into the same 10-day-old piglet. Portal hypertension and translocation of human iPSC-derived liver organoids to the lungs were observed in one of two transplanted animals. Translocation occurred in the piglet in which patent ductus venosus (PDV) was observed. Therefore, a 28-day-old piglet capable of surgically ligating PDV was used, and after the PDV was ligated, human iPSC-derived liver organoids with the amount of which is scheduled in clinical trials were transplanted. This procedure inhibited the translocation of human iPSC-derived liver organoids to extrahepatic sites without no portal hypertension. In conclusion, human iPSC-derived liver organoids can be safely transplanted through the portal vein. Ligation of the ductus venosus prior to transplantation was effective in inhibiting extrahepatic translocation in newborns and infants.
肝类器官移植已被研究作为慢性肝病肝移植的替代治疗方法。经门脉途径可以被认为是将类器官递送到肝脏的一种方法。重要的是要设定允许的类器官数量，并通过门静脉内移植来验证转位。我们首先使用仔猪检查了来自猪胎儿肝的同种异体类器官的移植耐受和转位。通过门静脉左支将来自 Kusabira Orange 转导猪的胎儿肝衍生的类器官移植到 10 日龄仔猪的肝脏。所有受者均存活，没有任何观察到的不良事件。相反，在移植过程中，局部和主门静脉压均短暂升高。在尸检样本中，Kusabira Orange 阳性供体细胞主要在靶肝叶中检测到，部分在其他区域（包括肺和脑）中检测到。由于我们通过猪胎儿肝衍生的类器官确认了移植允许量，因此我们进行了门静脉内移植计划用于临床试验的人诱导多能干细胞（iPSC）衍生的肝类器官，并研究了门静脉压和转位。将人 iPSC 衍生的肝类器官移植到相同的 10 日龄仔猪中。在两个移植动物中的一个中观察到门静脉高压和人 iPSC 衍生的肝类器官向肺部的转位。在观察到卵圆孔未闭（PDV）的仔猪中转位发生。因此，使用了能够进行 PDV 结扎的 28 日龄仔猪，并且在 PDV 结扎后，移植了临床试验中计划使用的数量的人 iPSC 衍生的肝类器官。该程序抑制了人 iPSC 衍生的肝类器官向肝外部位的转位，而没有门静脉高压。总之，人 iPSC 衍生的肝类器官可以通过门静脉安全地移植。在移植前结扎静脉导管可有效抑制新生儿和婴儿的肝外转位。
