Liver injury associated with acute graft-versus-host disease (aGVHD) is a frequent and severe complication of hematopoietic stem cell transplantation and remains a major cause of transplant-related mortality. Bone marrow-derived mesenchymal stem cells (BM-MSCs) has been proposed as a potential therapeutic approach for aGVHD. However, the therapeutic effects are not always achieved. In this study, we genetically engineered C57BL/6 mouse BM-MSCs with AKT1 gene and tested whether AKT1-MSCs was superior to control MSCs (Null-MSCs) for cell therapy of liver aGVHD. In vitro apoptosis analyses showed that, under both routine culture condition and high concentration interferon-γ (IFN-γ) (100ng/mL) stimulation condition, AKT1-MSCs had a survival (anti-apoptotic) advantage compared to Null-MSCs. In vivo imaging showed that AKT1-MSCs had better homing capacity and longer persistence in injured liver compared to Null-MSCs. Most importantly, AKT1-MSCs demonstrated an enhanced immunomodulatory function by releasing more immunosuppressive cytokines, such as IL-10. Adoptive transfer of AKT1-MSCs mitigated the histopathological abnormalities of concanavalin A(ConA)-induced liver injury along with significantly lowered serum levels of ALT and AST. The attenuation of liver injury correlated with the decrease of TNF-α and IFN-γ both in liver tissue and in the serum. In summary, BM-MSCs genetically modified with AKT1 has a survival advantage and an enhanced immunomodulatory function both in vitro and in vivo and thus demonstrates the therapeutic potential for prevention and amelioration of liver GVHD and other immunity-associated liver injuries.

中文翻译：

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用 Akt1 修饰的骨髓来源的间充质干细胞可改善急性肝 GVHD

与急性移植物抗宿主病 (aGVHD) 相关的肝损伤是造血干细胞移植的常见且严重的并发症，并且仍然是移植相关死亡率的主要原因。骨髓来源的间充质干细胞 (BM-MSCs) 已被提议作为 aGVHD 的潜在治疗方法。然而，治疗效果并不总能达到。在这项研究中，我们对具有 AKT1 基因的 C57BL/6 小鼠 BM-MSCs 进行了基因工程，并测试了 AKT1-MSCs 在肝脏 aGVHD 细胞治疗方面是否优于对照 MSCs (Null-MSCs)。体外凋亡分析表明，在常规培养条件和高浓度干扰素-γ (IFN-γ) (100ng/mL) 刺激条件下，AKT1-MSCs 与 Null-MSCs 相比具有存活（抗凋亡）优势。体内成像显示，与 Null-MSCs 相比，AKT1-MSCs 在受损肝脏中具有更好的归巢能力和更长的持续时间。最重要的是，AKT1-MSCs 通过释放更多的免疫抑制细胞因子（如 IL-10）表现出增强的免疫调节功能。AKT1-MSCs 的过继转移减轻了伴刀豆球蛋白 A（ConA）诱导的肝损伤的组织病理学异常，同时显着降低了血清 ALT 和 AST 水平。肝损伤的减轻与肝组织和血清中 TNF-α 和 IFN-γ 的减少有关。总之，用 AKT1 基因修饰的 BM-MSCs 在体外和体内都具有生存优势和增强的免疫调节功能，因此证明了预防和改善肝脏 GVHD 和其他免疫相关肝损伤的治疗潜力。