Transplant Division, Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Cell Transplant. 2021 Jan-Dec;30:963689721993780. doi: 10.1177/0963689721993780.
Stem cell transplantation to the liver is a promising therapeutic strategy for a variety of disorders. Hepatocyte transplantation has short-term efficacy but can be problematic due to portal hypertension, inflammation, and sinusoidal thrombosis. We have previously transplanted small mouse endoderm progenitor (EP) cells to successfully reverse a murine model of hemophilia B, and labeling these cells with iron nanoparticles renders them responsive to magnetic fields, which can be used to enhance engraftment. The mechanisms mediating progenitor cell migration from the sinusoidal space to the hepatocyte compartment are unknown. Here we find human EP and hepatic progenitor (HP) cells can be produced from human embryonic stem cells with high efficiency, and they also readily uptake iron nanoparticles. This provides a simple manner through which one can readily identify transplanted cells in vivo using electron microscopy, shortly after delivery. High resolution imaging shows progenitor cell morphologies consistent with epithelial-to-mesenchymal transition (EMT) mediating invasion into the hepatic parenchyma. This occurs in as little as 3 h, which is considerably faster than observed when hepatocytes are transplanted. We confirmed activated EMT in transplanted cells in vitro, as well as in vivo 24 h after transplantation. We conclude that EMT naturally occurs concurrent with EP and HP cell engraftment, which may mediate the rate, safety, and efficacy of early cell engraftment in the undamaged quiescent liver.
肝干细胞移植是治疗多种疾病的一种很有前途的治疗策略。肝细胞移植具有短期疗效，但由于门静脉高压、炎症和窦状隙血栓形成，可能会出现问题。我们之前已经成功地将小的鼠内胚层祖细胞（EP）移植到患有血友病 B 的鼠模型中，并且用铁纳米粒子对这些细胞进行标记，使其对磁场有反应，从而可以增强移植细胞的植入效果。介导祖细胞从窦状隙空间迁移到肝细胞区室的机制尚不清楚。在这里，我们发现人胚胎干细胞可以高效地产生人 EP 和肝祖细胞（HP），并且它们也容易摄取铁纳米粒子。这提供了一种简单的方法，可以在递送后不久使用电子显微镜在体内轻易地识别移植细胞。高分辨率成像显示祖细胞形态与上皮-间充质转化（EMT）一致，介导其侵入肝实质。这一过程仅需 3 小时，比移植肝细胞时观察到的速度要快得多。我们在体外和移植后 24 小时在体内证实了移植细胞中的 EMT 被激活。我们得出结论，EMT 与 EP 和 HP 细胞的植入同时发生，这可能介导了受损静止肝脏中早期细胞植入的速度、安全性和疗效。
