Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Heidelberg University, German Red Cross Blood Service Baden-Württemberg-Hessen, 68167 Mannheim, Germany.
FlowCore Mannheim Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Cells. 2020 Nov 5;9(11):2419. doi: 10.3390/cells9112419.
Over recent years, mesenchymal stromal cells (MSC) have gained immense attraction in immunotherapy, regenerative medicine and tissue engineering. MSC microenvironment modulation occurs through synergy of direct cell-cell contact, and secreted soluble factors and extracellular vesicles (EV). MSC-derived EV have been suggested as cell-free immunomodulatory alternative to MSC; however, previous findings have challenged this. Furthermore, recent data suggest that evaluating the mechanism of action of human MSC (hMSC) in animal models might promote adverse immune reactions or lack of functionality due to xeno-incompatibilities. In this study, we first assessed the immunomodulatory strength of different human MSC sources on in vitro stimulated T cells and compared this to interferon-gamma (IFNγ) primed MSC conditioned medium (CM) and EV. Second, we addressed the main molecular mechanisms, and third, we assessed the MSC in vitro immunosuppressive effect across interspecies barriers. We identified human adipose tissue-derived stromal cells (ASC) with strongest immunomodulatory strength, followed by bone marrow (BM) and cord blood-derived MSC (CB). Whilst CM from primed ASC managed to exert analogous effects as their cellular counterpart, EV derived thereof did not, reproducing previous findings. IFNγ-induced indoleamine 2,3-dioxygenase (IDO) activity was identified as key mechanism to suppress human lymphocyte proliferation, as in the presence of the IDO inhibitor epacadostat (Epac) a stimulation of proliferation was seen. In addition, we revealed MSC immunosuppressive effects to be species-specific, because human cells failed to suppress murine lymphocyte proliferation. In summary, ASC were the strongest immunomodulators with the IDO-kynurenine pathway being key within the human system. Importantly, the in vitro lack of interspecies immunomodulatory strength suggests that preclinical data need to be carefully interpreted especially when considering a possible translation to clinical field.
近年来，间充质基质细胞（MSC）在免疫疗法、再生医学和组织工程领域引起了极大的关注。MSC 微环境的调节是通过直接的细胞-细胞接触以及分泌的可溶性因子和细胞外囊泡（EV）的协同作用实现的。MSC 衍生的 EV 已被认为是 MSC 无细胞免疫调节的替代物；然而，之前的研究结果对此提出了挑战。此外，最近的数据表明，在动物模型中评估人 MSC（hMSC）的作用机制可能会由于异种不兼容性而促进不良反应或缺乏功能。在这项研究中，我们首先评估了不同人 MSC 来源对体外刺激的 T 细胞的免疫调节强度，并将其与干扰素-γ（IFNγ）预刺激 MSC 条件培养基（CM）和 EV 进行了比较。其次，我们解决了主要的分子机制问题，最后，我们评估了 MSC 在种间屏障下的体外免疫抑制作用。我们确定了具有最强免疫调节强度的人脂肪组织来源基质细胞（ASC），其次是骨髓（BM）和脐血来源的 MSC（CB）。虽然预刺激 ASC 的 CM 能够发挥与其细胞对应物类似的作用，但衍生的 EV 却没有，这与之前的研究结果一致。IFNγ 诱导的吲哚胺 2,3-双加氧酶（IDO）活性被确定为抑制人淋巴细胞增殖的关键机制，因为在 IDO 抑制剂 epacadostat（Epac）存在的情况下，观察到增殖的刺激。此外，我们揭示了 MSC 的免疫抑制作用是种属特异性的，因为人类细胞不能抑制鼠类淋巴细胞的增殖。总之，ASC 是最强的免疫调节剂，IDO-犬尿氨酸途径是人类系统中的关键途径。重要的是，体外缺乏种间免疫调节强度表明，特别是在考虑将其转化为临床领域时，需要仔细解释临床前数据。
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