Endometrial regeneration cell-derived exosomes loaded with siSLAMF6 inhibit cardiac allograft rejection through the suppression of desialylation modification.

IF 9.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yini Xu, Shaohua Ren, Hongda Wang, Yafei Qin, Tong Liu, Chenglu Sun, Yiyi Xiao, Bo Shao, Jingyi Zhang, Qiang Chen, Pengyu Zhao, Guangmei Yang, Xu Liu, Hao Wang
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引用次数: 0

Abstract

Backgrounds: Acute transplant rejection is a major component of poor prognoses for organ transplantation. Owing to the multiple complex mechanisms involved, new treatments are still under exploration. Endometrial regenerative cells (ERCs) have been widely used in various refractory immune-related diseases, but the role of ERC-derived exosomes (ERC-Exos) in alleviating transplant rejection has not been extensively studied. Signaling lymphocyte activation molecule family 6 (SLAMF6) plays an important role in regulating immune responses. In this study, we explored the main mechanism by which ERC-Exos loaded with siSLAMF6 can alleviate allogeneic transplant rejection.

Methods: C57BL/6 mouse recipients of BALB/c mouse kidney transplants were randomly divided into four groups and treated with exosomes. The graft pathology was evaluated by H&E staining. Splenic and transplanted heart immune cell populations were analyzed by flow cytometry. Recipient serum cytokine profiles were determined by enzyme-linked immunosorbent assay (ELISA). The proliferation and differentiation capacity of CD4+ T cell populations were evaluated in vitro. The α-2,6-sialylation levels in the CD4+ T cells were determined by SNA blotting.

Results: In vivo, mice treated with ERC-siSLAMF6 Exo achieved significantly prolonged allograft survival. The serum cytokine profiles of the recipients were significantly altered in the ERC-siSLAMF6 Exo-treated recipients. In vitro, we found that ERC-siSLAMF6-Exo considerably downregulated α-2,6-sialyltransferase (ST6GAL1) expression in CD4+ T cells, and significantly reduced α-2,6-sialylation levels. Through desialylation, ERC-siSLAMF6 Exo therapy significantly decreased CD4+ T cell proliferation and inhibited CD4+ T cell differentiation into Th1 and Th17 cells while promoting regulatory T cell (Treg) differentiation.

Conclusions: Our study indicated that ERC-Exos loaded with siSLAMF6 reduce the amount of sialic acid connected to α-2,6 at the end of the N-glycan chain on the CD4+ T cell surface, increase the number of therapeutic exosomes endocytosed into CD4+ T cells, and inhibit the activation of T cell receptor signaling pathways, which prolongs allograft survival. This study confirms the feasibility of using ERC-Exos as natural carriers combined with gene therapy, which could be used as a potential therapeutic strategy to alleviate allograft rejection.

装载了 siSLAMF6 的子宫内膜再生细胞衍生外泌体可通过抑制去酰化修饰抑制心脏异体移植排斥反应。
背景:急性移植排斥反应是器官移植预后不良的主要原因之一。由于涉及多种复杂机制,新的治疗方法仍在探索之中。子宫内膜再生细胞(ERC)已被广泛用于各种难治性免疫相关疾病,但ERC衍生的外泌体(ERC-Exos)在缓解移植排斥反应方面的作用尚未得到广泛研究。信号淋巴细胞活化分子家族 6(SLAMF6)在调节免疫反应中发挥着重要作用。在这项研究中,我们探讨了装载siSLAMF6的ERC-Exos减轻异体移植排斥反应的主要机制:方法:将接受 BALB/c 小鼠肾移植的 C57BL/6 小鼠随机分为四组,并用外泌体治疗。用 H&E 染色法评估移植物病理学。用流式细胞术分析脾脏和移植心脏免疫细胞群。受体血清细胞因子谱通过酶联免疫吸附试验(ELISA)测定。体外评估了 CD4+ T 细胞群的增殖和分化能力。用 SNA 印迹法测定 CD4+ T 细胞中的α-2,6-糖基化水平:结果:在体内,接受ERC-siSLAMF6 Exo治疗的小鼠的异体移植存活时间明显延长。经ERC-siSLAMF6 Exo处理的受者血清细胞因子谱发生了显著变化。在体外,我们发现ERC-siSLAMF6-Exo能显著下调CD4+ T细胞中α-2,6-氨酰基转移酶(ST6GAL1)的表达,并显著降低α-2,6-氨酰基化水平。通过去ialylation,ERC-siSLAMF6 Exo疗法能显著降低CD4+ T细胞的增殖,抑制CD4+ T细胞向Th1和Th17细胞分化,同时促进调节性T细胞(Treg)分化:我们的研究表明,装载siSLAMF6的ERC-外泌体能减少CD4+ T细胞表面N-糖链末端与α-2,6相连的sialic酸的数量,增加内吞到CD4+ T细胞中的治疗外泌体的数量,抑制T细胞受体信号通路的激活,从而延长异体移植的存活时间。这项研究证实了将ERC-外泌体作为天然载体与基因疗法相结合的可行性,可将其作为一种潜在的治疗策略来缓解异体移植排斥反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular & Molecular Biology Letters
Cellular & Molecular Biology Letters 生物-生化与分子生物学
CiteScore
11.60
自引率
13.30%
发文量
101
审稿时长
3 months
期刊介绍: Cellular & Molecular Biology Letters is an international journal dedicated to the dissemination of fundamental knowledge in all areas of cellular and molecular biology, cancer cell biology, and certain aspects of biochemistry, biophysics and biotechnology.
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