Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis
Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis
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DOI：
10.1136/annrheumdis-2011-200985
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发表时间：
2012-10-01
影响因子：
27.4
通讯作者：
Yannaki, Evangelia
中科院分区：
文献类型：
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作者：
Papadopoulou, Anastasia;Yiangou, Minas;Yannaki, Evangelia
目的 间充质干细胞（MSC）在实验性关节炎中的作用无疑是存在争议的。本研究在之前未经测试且发病机制不同的类风湿关节炎（RA）模型中探究了骨髓来源的MSC的作用。
方法 在诱导性（佐剂诱导）和自发性（K/BxN）关节炎模型中对MSC进行测试。从临床和组织学方面对关节炎进行评估。通过放射性掺入法测量在有MSC存在的情况下脾细胞和成纤维样滑膜细胞（FLS）的增殖。通过实时聚合酶链反应（PCR）测量Toll样受体（TLR）的表达。通过流式细胞术监测调节性T细胞（Treg）频率、T细胞凋亡和细胞因子分泌。
结果 在体外，MSC强烈抑制关键细胞群，即脾细胞和FLS。相反，在体内MSC被证明是无效的，除非在疾病发作前给药，这一效应意味着炎性关节炎环境可能会消除MSC的免疫调节特性。为了在MSC输注前减轻炎症，作者在关节炎发病时给予一个短疗程的蛋白酶体抑制剂硼替佐米，而在预计疾病已形成时输注MSC。硼替佐米加MSC组相较于关节炎组、仅用MSC组和仅用硼替佐米组，关节炎评分显著降低，这也通过组织学和免疫组织化学得到了证实。硼替佐米加MSC组合恢复了血液中TLR的表达和Treg频率，并使FLS和脾细胞的增殖、凋亡以及细胞因子分泌恢复正常。
结论 当在自身免疫性关节炎的炎性微环境中输注MSC时，其会失去免疫调节特性。用硼替佐米对受体进行预处理可改变疾病微环境，使MSC能够调节关节炎。如果环境限制在人类疾病中也起作用，这种方法可作为一种用MSC治疗RA的策略。
Objective The role of mesenchymal stem cells (MSC) in experimental arthritis is undoubtedly conflicting. This study explored the effect of bone marrow-derived MSC in previously untested and pathogenetically different models of rheumatoid arthritis (RA).Methods MSC were tested both in an induced (adjuvant-induced) and a spontaneous (K/BxN) arthritis model. Arthritis was assessed clinically and histologically. The proliferation of splenocytes and fibroblast-like synoviocytes (FLS) in the presence of MSC was measured by radioactivity incorporation. Toll-like receptor (TLR) expression was measured by real-time PCR. T-regulatory cell (Treg) frequency, T-cell apoptosis and cytokine secretion were monitored by flow cytometry.Results MSC, in vitro, strongly inhibited critical cell populations; splenocytes and FLS. In contrast, MSC proved ineffective in vivo, unless they were administered before disease onset, an effect implying that the inflammatory arthritic milieu potentially abrogates MSC immunomodulatory properties. In order to alleviate inflammation before MSC infusion, the authors administered, at arthritis onset, a short course with a proteasome inhibitor, bortezomib, whereas MSC were infused when established disease was expected. The bortezomib plus MSC group demonstrated a significantly decreased arthritis score over arthritic, MSC-only, bortezomib-only groups, also confirmed by histology and immunohistochemistry. The bortezomib plus MSC combination restored TLR expression and Treg frequency in blood and normalised FLS and splenocyte proliferation, apoptosis and cytokine secretion.Conclusion MSC lose their immunomodulatory properties when infused in the inflammatory micromilieu of autoimmune arthritis. Conditioning of the recipient with bortezomib alters the disease microenvironment enabling MSC to modulate arthritis. Should milieu limitations also operate in human disease, this approach could serve as a strategy to treat RA by MSC.