Department of General Surgery, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin, 300052, China.
Tianjin General Surgery Institute, Tianjin, 300052, China.
Stem Cell Res Ther. 2020 Jun 17;11(1):241. doi: 10.1186/s13287-020-01752-1.
Mesenchymal stem cells (MSCs) have become a promising candidate for cell-based immune therapy for acute rejection (AR) after heart transplantation due to possessing immunomodulatory properties. In this study, we evaluated the efficacy of soluble fibronectin-like protein 2 (sFgl2) overexpressing mesenchymal stem cells (sFgl2-MSCs) in inhibiting AR of heart transplantation in mice by regulating immune tolerance through inducing M2 phenotype macrophage polarization.
The sFgl2, a novel immunomodulatory factor secreted by regulatory T cells, was transfected into MSCs to enhance their immunosuppressive functions. After being co-cultured for 72 h, the sFgl2-MSCs inhibited M1 polarization whereas promoted M2 of polarization macrophages through STAT1 and NF-κB pathways in vitro. Besides, the sFgl2-MSCs significantly enhanced the migration and phagocytosis ability of macrophages stimulated with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Further, the application potential of sFgl2-MSCs in AR treatment was demonstrated by heterotopic cardiac transplantation in mice. The tissue damage and macrophage infiltration were evaluated by H&E and immunohistochemistry staining, and the secretion of inflammatory cytokines was analyzed by ELISA. The results showed that sFgl2-MSCs injected intravenously were able to locate in the graft, promote the M2 polarization of macrophages in vivo, regulate the local and systemic immune response, significantly protect tissues from damaging, and finally prolonged the survival time of mice heart grafts.
sFgl2-MSCs ameliorate AR of heart transplantation by regulating macrophages, which provides a new idea for the development of anti-AR treatment methods after heart transplantation.
间充质干细胞（MSCs）由于具有免疫调节特性，已成为心脏移植后基于细胞的免疫治疗急性排斥（AR）的有前途的候选物。在这项研究中，我们通过诱导 M2 表型巨噬细胞极化来调节免疫耐受，评估了过表达可溶性纤维连接蛋白样蛋白 2（sFgl2）的间充质干细胞（sFgl2-MSCs）通过调节免疫耐受抑制心脏移植后 AR 的功效。
sFgl2 是调节性 T 细胞分泌的新型免疫调节因子，将其转染到 MSCs 中以增强其免疫抑制功能。共培养 72 小时后，sFgl2-MSCs 通过 STAT1 和 NF-κB 途径抑制 M1 极化，而促进极化巨噬细胞的 M2。此外，sFgl2-MSCs 显著增强了干扰素-γ（IFN-γ）和脂多糖（LPS）刺激的巨噬细胞的迁移和吞噬能力。此外，通过在小鼠异位心脏移植中证明了 sFgl2-MSCs 在 AR 治疗中的应用潜力。通过 H&E 和免疫组化染色评估组织损伤和巨噬细胞浸润，通过 ELISA 分析炎症细胞因子的分泌。结果表明，静脉注射的 sFgl2-MSCs 能够定位在移植物中，促进体内巨噬细胞的 M2 极化，调节局部和全身免疫反应，显著保护组织免受损伤，最终延长小鼠心脏移植物的存活时间。
sFgl2-MSCs 通过调节巨噬细胞改善心脏移植的 AR，为心脏移植后抗 AR 治疗方法的发展提供了新的思路。
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