Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Science, Beijing, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
Am J Transplant. 2023 Dec;23(12):1832-1844. doi: 10.1016/j.ajt.2023.07.020. Epub 2023 Jul 31.
Hepatocyte transplantation has the potential to treat acute liver failure and correct liver-based metabolic disorders. Proliferating human hepatocytes (ProliHHs) provide a large-scale source as an alternative to primary human hepatocytes. However, host rejection led to inefficient graft survival and function, which hindered the clinical application of cell therapy. Herein, we employed the lentiviral system to overexpress immunomodulatory factors programmed death-ligand 1 (cluster of differentiation 274) (CD274) and cluster of differentiation 47 (CD47) in ProliHHs. CD47+274 overexpression inhibited macrophage and T cell responses in vitro. After transplantation into mice via the spleen without immunosuppression, CD47+274 ProliHHs accumulation in the liver significantly increased for 48 hours compared with ProliHHs. Consistent with the in vitro results, CD47+274 ProliHHs were less aggregated and infiltrated by macrophages and also recruited fewer T cells in the liver. Seven days after transplantation, the human albumin level of engineered ProliHHs doubled compared with control group. CD47+274 ProliHHs further ameliorated the liver injury induced using concanavalin A. Overall, our results suggested CD47+274 overexpression reduced innate and adaptive immune responses during hepatocyte transplantation, and the survival rate and graft function of transplanted hepatocyte-like cells were all significantly improved.
肝细胞移植有可能治疗急性肝衰竭和纠正基于肝脏的代谢紊乱。增殖的人肝细胞（ProliHHs）作为原代人肝细胞的替代物提供了大规模的来源。然而，宿主排斥反应导致移植物存活率和功能低下，从而阻碍了细胞治疗的临床应用。在此，我们采用慢病毒系统在 ProliHHs 中过表达免疫调节因子程序性死亡配体 1（分化群 274）（CD274）和分化群 47（CD47）。CD47+274 的过表达抑制了体外巨噬细胞和 T 细胞的反应。在未进行免疫抑制的情况下通过脾脏移植到小鼠体内后，与 ProliHHs 相比，CD47+274 ProliHHs 在肝脏中的聚集在 48 小时内显著增加。与体外结果一致，CD47+274 ProliHHs 较少被巨噬细胞聚集和浸润，在肝脏中也招募了较少的 T 细胞。移植后 7 天，工程化 ProliHHs 的人白蛋白水平是对照组的两倍。CD47+274 ProliHHs 进一步改善了伴刀豆球蛋白 A 诱导的肝损伤。总体而言，我们的研究结果表明，CD47+274 的过表达减少了肝细胞移植过程中的固有和适应性免疫反应，并且移植的肝样细胞的存活率和移植物功能均得到了显著改善。
