Adipose Tissue-Derived Stem Cells Suppress Acute Cellular Rejection by TSG-6 and CD44 Interaction in Rat Kidney Transplantation
Adipose Tissue-Derived Stem Cells Suppress Acute Cellular Rejection by TSG-6 and CD44 Interaction in Rat Kidney Transplantation
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DOI：
10.1097/tp.0000000000000230
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发表时间：
2014-08-15
期刊：
影响因子：
6.2
通讯作者：
Nonomura, Norio
中科院分区：
文献类型：
--
作者：
Kato, Taigo;Okumi, Masayoshi;Nonomura, Norio
背景除了其丰富和容易获得之外，脂肪组织产生比骨髓更有效的免疫调节干细胞（脂肪组织来源的干细胞，ADSC）。然而，ADSC对同种异体反应性的有益作用几乎不为人知。本研究旨在评价脂肪干细胞在大鼠肾移植中的作用，并分析其分子机制。将深色Agglutination大鼠肾脏移植到刘易斯大鼠中。在肾切除术前通过供体的左肾动脉注射自体ADSC（2 × 10（6））（ADSC组）。移植物存活率，组织学变化，以及几种细胞因子和蛋白质的表达进行了评估。在体外实验中，在混合淋巴细胞反应中测试ADSC的免疫抑制能力。组织学结果显示，与对照组相比，ADSC组的排斥反应等级降低，而浸润的CD 4（+）/CD 8（+）T细胞的数量也显著减少。相对于这些发现，注射ADSC导致与对照相比显著延长的平均移植物存活。在体外，自体ADSC剂量依赖性地抑制同种异体反应性淋巴细胞。此外，脂肪干细胞还能提高混合淋巴细胞反应中肿瘤坏死因子诱导基因6蛋白（TSG-6）的水平，具有抗炎作用。重组TSG-6通过下调CD 44表达，抑制同种异体反应性T细胞的活化和浸润。我们的研究结果清楚地表明，脂肪干细胞通过分泌TSG-6以及通过直接细胞相互作用来减轻急性排斥反应。这些发现有助于这些细胞在实体器官移植中的临床应用。
Background. In addition to its abundance and easy accessibility, adipose tissue yields more potent immunoregulatory stem cells (adipose tissue-derived stem cells, ADSCs) than does bone marrow. However, the beneficial effects of ADSCs on alloreactivity are scarcely known. This study evaluated the beneficial effects of ADSCs in rat kidney transplantation and analyzed the underlying molecular mechanism.Methods. Dark Agouti rat kidneys were transplanted into Lewis rats. Autologous ADSCs (2 x 10(6)) were injected through the left renal artery of the donors before the nephrectomy (ADSCs group). Graft survival, histologic changes, and the expression of several cytokines and proteins were assessed. In an in vitro experiment, the immunosuppressive capacity of ADSCs was tested in a mixed lymphocyte reaction.Results. Histologic findings of the ADSCs group revealed a reduced rejection grade, whereas the number of infiltrated CD4(+)/CD8(+) T cells was also significantly decreased as compared to the control. Relative to these findings, injection of ADSCs led to a significantly prolonged mean graft survival compared with the control. In vitro, autologous ADSCs dose-dependently suppressed alloreactive lymphocytes. Moreover, ADSCs increased the level of tumor necrosis factor-inducible gene 6 protein (TSG-6) in mixed lymphocyte reaction, which has an anti-inflammatory capacity. Recombinant TSG-6 markedly suppressed alloreactive T cells through downregulating CD44, which may lead to the suppression of T-cell activation and infiltration into allografts.Conclusion. Our findings clearly showed that ADSCs attenuated acute rejection by secreting TSG-6 as well as through direct cell interaction. These findings contribute to the clinical application of these cells in solid organ transplantation.