Chen Zheng, Niu Minghui, Sun Min, Yuan Qingqing, Yao Chencheng, Hou Jingmei, Wang Hong, Wen Liping, Fu Hongyong, Zhou Fan, Li Zheng, He Zuping
State Key Laboratory of Oncogenes and Related Genes, Renji- Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Department of General Surgery, Suqian people's Hospital, The Affiliated Hospital of Xuzhou Medical University, Jiangsu 223800, China.
Oncotarget. 2017 Feb 28;8(9):14576-14592. doi: 10.18632/oncotarget.14713.
Here we proposed a new concept that human spermatogonial stem cells (SSCs) can transdifferentiate into hepatocytes in vivo. We first established liver injury model of mice by carbon tetrachloride to provide proper environment for human SSC transplantation. Liver mesenchymal cells were isolated from mice and identified phenotypically. Human SSC line was recombined with liver mesenchymal cells, and they were transplanted under renal capsules of nude mice with liver injury. The grafts expressed hepatocyte hallmarks, including ALB, AAT, CK18, and CYP1A2, whereas germ cell and SSC markers VASA and GPR125 were undetected in these cells, implicating that human SSCs were converted to hepatocytes. Furthermore, Western blots revealed high levels of PCNA, AFP, and ALB, indicating that human SSCs-derived hepatocytes had strong proliferation potential and features of hepatocytes. In addition, ALB-, CK8-, and CYP1A2- positive cells were detected in liver tissues of recipient mice. Significantly, no obvious lesion or teratomas was observed in several important organs and tissues of recipient mice, reflecting that transplantation of human SSCs was safe and feasible. Collectively, we have for the first time demonstrated that human SSCs can be transdifferentiated to hepatocyte in vivo. This study provides a novel approach for curing liver diseases using human SSC transplantation.
在此，我们提出了一个新的概念，即人类精原干细胞（SSCs）可在体内转分化为肝细胞。我们首先通过四氯化碳建立小鼠肝损伤模型，为人类SSC移植提供适宜的环境。从小鼠体内分离肝间充质细胞并进行表型鉴定。将人类SSC系与肝间充质细胞重组，然后将它们移植到有肝损伤的裸鼠肾被膜下。移植细胞表达肝细胞标志物，包括白蛋白（ALB）、α1抗胰蛋白酶（AAT）、细胞角蛋白18（CK18）和细胞色素P450 1A2（CYP1A2），而在这些细胞中未检测到生殖细胞和SSC标志物血管生殖蛋白（VASA）和G蛋白偶联受体125（GPR125），这表明人类SSCs已转化为肝细胞。此外，蛋白质免疫印迹分析显示增殖细胞核抗原（PCNA）、甲胎蛋白（AFP）和ALB水平较高，表明人类SSCs来源的肝细胞具有较强的增殖潜能和肝细胞特征。另外，在受体小鼠的肝组织中检测到ALB、细胞角蛋白8（CK8）和CYP1A2阳性细胞。值得注意的是，在受体小鼠的几个重要器官和组织中未观察到明显病变或畸胎瘤，这反映出人类SSCs移植是安全可行的。总体而言，我们首次证明了人类SSCs可在体内转分化为肝细胞。本研究为利用人类SSC移植治疗肝脏疾病提供了一种新方法。
