Song Yunejin, Lim Jung-Yeon, Lim Taekyu, Im Keon-Il, Kim Nayoun, Nam Young-Sun, Jeon Young-Woo, Shin Jong Chul, Ko Hyun Sun, Park In Yang, Cho Seok-Goo
Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.
Division of Hematology Oncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul 05368, South Korea.
World J Stem Cells. 2020 Sep 26;12(9):1032-1049. doi: 10.4252/wjsc.v12.i9.1032.
Mesenchymal stem cells (MSCs) are an attractive tool to treat graft-versus-host disease because of their unique immunoregulatory properties. Although human bone marrow-derived MSCs (BM-MSCs) were the most widely used MSCs in cell therapy until recently, MSCs derived from human umbilical cords (UC-MSCs) have gained popularity as cell therapy material for their ethical and noninvasive collection.
To investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.
To analyze soluble factors expressed by MSCs, such as indolamine 2,3-dioxygenase, cyclooxygenase-2, prostaglandin E2 and interleukin (IL)-6, inflammatory environments were reconstituted with combinations of interferon-gamma (IFN-γ), tumor necrosis factor alpha and IL-1β or with IFN-γ alone. Activated T cells were cocultured with MSCs treated with indomethacin and/or anti-IL-10. To assess the ability of MSCs to inhibit T helper 17 cells and induce regulatory T cells, induced T helper 17 cells were cocultured with MSCs treated with indomethacin or anti-IL-10. Xenogeneic graft-versus-host disease was induced in NOG mice (NOD/Shi-/IL-2Rγ) and UC-MSCs or BM-MSCs were treated as cell therapies.
Our data demonstrated that BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunomodulation abilities. BM-MSCs expressed more indolamine 2,3-dioxygenase after cytokine stimulation with different combinations of IFN-γ, tumor necrosis factor alpha-α and IL-1β or IFN-γ alone. UC-MSCs expressed more prostaglandin E2, IL-6, programmed death-ligand 1 and 2 in the inflammatory environment. Cyclooxygenase-2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs. In addition, UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs. UC-MSCs and BM-MSCs exhibited similar effects on attenuating graft-versus-host disease.
UC-MSCs and BM-MSCs exert similar immunosuppressive effects with different mechanisms involved. These findings suggest that UC-MSCs have distinct immunoregulatory functions and may substitute BM-MBSCs in the field of cell therapy.
间充质干细胞（MSCs）因其独特的免疫调节特性，是治疗移植物抗宿主病的一种有吸引力的工具。尽管直到最近，人骨髓来源的间充质干细胞（BM-MSCs）仍是细胞治疗中使用最广泛的间充质干细胞，但人脐带来源的间充质干细胞（UC-MSCs）因其伦理和非侵入性采集方式，作为细胞治疗材料越来越受欢迎。
研究UC-MSCs和BM-MSCs免疫抑制作用机制的差异。
为分析间充质干细胞表达的可溶性因子，如吲哚胺2,3-双加氧酶、环氧化酶-2、前列腺素E2和白细胞介素（IL）-6，用γ干扰素（IFN-γ）、肿瘤坏死因子α和IL-1β联合或单独使用IFN-γ重建炎症环境。将活化的T细胞与用吲哚美辛和/或抗IL-10处理的间充质干细胞共培养。为评估间充质干细胞抑制辅助性T细胞17并诱导调节性T细胞的能力，将诱导的辅助性T细胞17与用吲哚美辛或抗IL-10处理的间充质干细胞共培养。在NOG小鼠（NOD/Shi-/IL-2Rγ）中诱导异种移植物抗宿主病，并将UC-MSCs或BM-MSCs作为细胞疗法进行处理。
我们的数据表明，BM-MSCs和UC-MSCs具有相似的表型特征和免疫调节能力。在用不同组合的IFN-γ、肿瘤坏死因子α-α和IL-1β联合或单独使用IFN-γ进行细胞因子刺激后，BM-MSCs表达更多的吲哚胺2,3-双加氧酶。在炎症环境中，UC-MSCs表达更多的前列腺素E2、IL-6、程序性死亡配体1和2。环氧化酶-2和IL-10是两种间充质干细胞免疫调节机制的关键因素。此外，UC-MSCs比BM-MSCs更能抑制辅助性T细胞17并诱导更多的调节性T细胞。UC-MSCs和BM-MSCs在减轻移植物抗宿主病方面表现出相似的效果。
UC-MSCs和BM-MSCs发挥相似的免疫抑制作用，但涉及不同的机制。这些发现表明，UC-MSCs具有独特的免疫调节功能，可能在细胞治疗领域替代BM-MBSCs。
