Human mesenchymal stem cells induce T cell anergy and downregulate T cell allo-responses via the TH2 pathway: Relevance to tissue engineering human heart valves
Human mesenchymal stem cells induce T cell anergy and downregulate T cell allo-responses via the TH2 pathway: Relevance to tissue engineering human heart valves
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DOI：
10.1089/ten.2006.12.2263
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发表时间：
2006-08-01
影响因子：
--
通讯作者：
Yacoub, Magdi H.
中科院分区：
文献类型：
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作者：
Batten, Puspa;Sarathchandra, Padmini;Yacoub, Magdi H.
为了制造“现成的”组织工程心脏瓣膜，细胞需要是同种异体的。在这里，我们报告的可能性，使用人骨髓间充质干细胞（MSC）作为一个合适的同种异体细胞来源的组织工程心脏瓣膜。检测了原代和致敏的CD 4（+）T细胞对同种异体MSC的增殖反应。蛋白质微阵列系统用于检测从T细胞测定收集的上清液中的可溶性因子。尽管提供了B7-1反式共刺激，但MSC是原代和致敏的CD 4（+）T细胞增殖的弱刺激剂，MSC不仅直接抑制了原代和致敏的T细胞对同种异体外周血单核细胞（PBMC）的反应，而且与MSC预培养24小时的T细胞以接触依赖性方式抑制了随后的T细胞对同种异体PBMC的增殖反应。上清液的分析揭示了与PBMC或内皮细胞相比，T细胞与MSC共培养后的细胞因子谱明显不同。促炎性Th 1细胞因子白细胞介素（IL）-1 α和β、干扰素（IFN）γ和肿瘤坏死因子（TNF）α下调，而抗炎性Th 2细胞因子IL-3、IL-6、IL-10和IL-13以及Th 2趋化因子I-309（调节性T细胞的化学引诱物）上调。进一步分析显示，与MSC共培养后，T细胞表现出调节表型（CD 4（+）CD 25（lo）CD 69（lo）FoxP 3（+））。MSC通过直接接触和分泌抗炎和致耐受性细胞因子下调T细胞应答，这可能涉及调节性T细胞的募集。这意味着同种异体间充质干细胞可能是组织工程心脏瓣膜的合适细胞来源。
To generate an "off the shelf" tissue-engineered heart valve, the cells would need to be of allogeneic origin. Here, we report the possibility of using human bone marrow-derived mesenchymal stem cells (MSCs) as a suitable allogeneic cell source for tissue-engineered heart valves. Proliferative responses of primary and primed CD4(+) T cells to allogeneic MSCs were examined. A protein microarray system was used to detect soluble factors from supernatants collected from the T cell assays. MSCs are poor stimulators of primary and primed CD4(+) T cell proliferation, despite provision of B7-1 trans-co-stimulation, MSCs not only directly inhibited primary and primed T cell responses to allogeneic peripheral blood mononuclear cells (PBMCs), but 24-h pre-culture of T cells with MSCs suppressed subsequent T cell proliferative responses to allogeneic PBMCs in a contact-dependent manner. Analysis of supernatants revealed a distinctly different cytokine profile after co-culture of T cells with MSCs than with PBMCs or endothelial cells. Pro-inflammatory Th1 cytokines interleukin (IL)-1 alpha and beta, interferon (IFN)gamma, and tumor necrosis factor (TNF)alpha were downregulated, whereas, anti-inflammatory Th2 cytokines IL-3, IL,6, IL-10, and IL-13 and the Th2 chemokine I-309, a chemoattractant for regulatory T cells, were upregulated. Further analysis revealed that after co-culture with MSCs, the T cells exhibited a regulatory phenotype (CD4(+)CD25(lo)CD69(lo)FoxP3(+)). MSCs downregulate T cell responses through direct contact and secretion of anti-inflammatory and tolerogenic cytokines, which may involve the recruitment of regulatory T cells. This implies that allogeneic MSCs could be a suitable cell source for tissue engineering a heart valve.