Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan (R.O.C.).
Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan (R.O.C.).
Transplantation. 2021 Apr 1;105(4):785-795. doi: 10.1097/TP.0000000000003461.
Hepatocyte transplantation has been extensively investigated as an alternative to orthotopic liver transplantation. However, its application in routine clinical practice has been restricted because of low initial engraftment and subsequent repopulation.
Using mice as a model, we have developed a minimally invasive and nontoxic preconditioning strategy based on preadministration of antibodies against hepsin to increase donor hepatocyte retention and engraftment rate.
Liver sinusoid diameters decreased significantly with antihepsin pretreatment, and graft cell numbers increased nearly 2-fold in the recipients' liver parenchyma for 20 days after hepatocyte transplantation. Postoperative complications such as hepatic ischemia injury or apparent immune cell accumulation were not observed in recipients. In a hemophilia B mouse model, antihepsin preconditioning enhanced the expression and clotting activity of coagulation factor IX (FIX) to nearly 2-fold that of immunoglobulin G-treated controls and maintained higher plasma FIX clotting activity relative to the prophylactic range for 50 days after hepatocyte transplantation. Antihepsin pretreatment combined with adeno-associated virus-transduced donor hepatocytes expressing human FIX-Triple, a hyperfunctional FIX variant, resulted in plasma FIX levels similar to those associated with mild hemophilia, which protected hemophilia B mice from major bleeding episodes for 50 days after transplantation. Furthermore, antihepsin pretreatment and repeated transplantation resulted in extending the therapeutic period by 30 days relative to the immunoglobulin G control.
Thus, this antihepsin strategy improved the therapeutic effect of hepatocyte transplantation in mice with tremendous safety and minimal invasion. Taken together, we suggest that preconditioning with antihepsin may have clinical applications for liver cell therapy.
肝细胞移植作为原位肝移植的替代方法已得到广泛研究。然而，由于初始植入率低和随后的再植入，其在常规临床实践中的应用受到限制。
我们使用小鼠作为模型，开发了一种微创且无毒的预处理策略，该策略基于预先给予针对组织蛋白酶 H 的抗体，以增加供体肝细胞的保留和植入率。
肝窦直径在用抗组织蛋白酶 H 预处理后显著减小，并且在肝细胞移植后 20 天，受体肝实质中的移植物细胞数量增加了近 2 倍。在受体中未观察到肝缺血损伤或明显的免疫细胞积聚等术后并发症。在乙型血友病小鼠模型中，抗组织蛋白酶 H 预处理增强了凝血因子 IX（FIX）的表达和凝血活性，使其接近 IgG 处理对照组的 2 倍，并且在肝细胞移植后 50 天内维持相对高于预防范围的较高血浆 FIX 凝血活性。抗组织蛋白酶 H 预处理与表达人 FIX-Triple 的腺相关病毒转导供体肝细胞相结合，FIX-Triple 是一种超功能 FIX 变体，导致血浆 FIX 水平类似于轻度血友病相关的水平，从而使乙型血友病小鼠在移植后 50 天内免受严重出血事件的影响。此外，与 IgG 对照组相比，抗组织蛋白酶 H 预处理和重复移植可将治疗期延长 30 天。
因此，这种抗组织蛋白酶 H 策略提高了肝细胞移植在小鼠中的治疗效果，且具有巨大的安全性和微创性。综上所述，我们认为抗组织蛋白酶 H 预处理可能具有肝细胞治疗的临床应用前景。
