Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
Tianjin General Surgery Institute, Tianjin, China.
Stem Cell Res Ther. 2022 Jul 15;13(1):302. doi: 10.1186/s13287-022-02982-1.
Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study.
C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay.
Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients.
IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.
子宫内膜再生细胞（ERCs）在减轻急性同种异体移植物排斥反应方面发挥着重要作用，但其作用有限。IL-37 是一种新发现的 IL-1 家族免疫调节细胞因子，可调节固有免疫和适应性免疫。IL-37 过表达是否能增强 ERC 抑制急性心脏同种异体排斥反应的治疗效果尚不清楚，本研究将对此进行探讨。
将接受 BALB/c 小鼠异位心脏同种异体移植的 C57BL/6 小鼠受体随机分为磷酸盐缓冲液（未处理）、ERC 处理、阴性慢病毒对照 ERC（NC-ERC）处理和 IL-37 过表达 ERC（IL-37-ERC）处理组。通过 H&E 染色评估移植物的病理变化。通过免疫组化和流式细胞术分别分析移植物内细胞浸润和脾免疫细胞群。通过 MLR 测定检测受者 DC 的刺激特性。此外，通过 ELISA 测定测量受者的血清细胞因子谱。
与 ERC 处理组相比，接受 IL-37-ERCs 治疗的小鼠的移植物存活时间明显延长。与所有其他对照组相比，IL-37-ERC 处理组显示炎症反应减轻，移植和脾脏中的耐受性树突状细胞（Tol-DCs）、调节性 T 细胞（Tregs）显著增加，而 Th1 和 Th17 细胞群减少。此外，在 IL-37-ERC 处理的受者血清中发现免疫调节 IL-10 显著上调，而 IFN-γ、IL-17A 和 IL-12 减少。
IL-37 过表达可促进 ERCs 的治疗效果，抑制急性同种异体排斥反应，进一步延长移植物存活时间。本研究表明，过表达 IL-37 的基因修饰 ERCs 可能为移植领域的新治疗选择铺平道路。
