Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system
Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system
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DOI：
10.1016/j.bbi.2015.06.024
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发表时间：
2015-11
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通讯作者：
L. S. Tejedor;G. Berner;K. Jacobsen;V. Gudi;N. Jungwirth;F. Hansmann;S. Gingele;C. K. Prajeeth;W. Baumgärtner;A. Hoffmann;T. Skripuletz;M. Stangel
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文献类型：
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作者：
L. S. Tejedor;G. Berner;K. Jacobsen;V. Gudi;N. Jungwirth;F. Hansmann;S. Gingele;C. K. Prajeeth;W. Baumgärtner;A. Hoffmann;T. Skripuletz;M. Stangel
再髓鞘化是脱髓鞘疾病如多发性硬化症（MS）的天然修复机制，并且提出其可以保护免于轴突损失。由于未知的原因，髓鞘再生在MS病变中通常是不完全的或失败的，并且增强髓鞘再生的治疗性治疗不可用。最近，移植外源性间充质干细胞（MSC）已成为一个有前途的工具，以加强修复过程。这包括动物模型实验性自身免疫性脑脊髓炎（EAE），MS的自身免疫机制的常用模型。然而，在EAE中，尚不清楚MSC的有益作用是否来自对脑驻留细胞的直接影响，或者这是否是通过调节外周免疫系统的间接现象。本研究的目的是确定MSC在脱髓鞘的毒性铜腙模型中的潜在再生功能，该模型允许研究对脱髓鞘和髓鞘再生的直接影响，而不影响外周免疫系统。将来自三种不同物种（人、鼠、犬）的MSC在两个时间点脑室内移植到脑脊液中或直接移植到胼胝体的病变中：在铜腙诱导的脱髓鞘期间，在少突胶质细胞祖细胞（OPC）增殖的开始或OPC增殖的峰值。我们的研究结果表明，MSC没有发挥任何再生作用后，cuprizone诱导脱髓鞘和少突胶质细胞损失。在髓鞘再生过程中，MSC不影响OPC增殖和髓鞘形成的动力学。总之，MSC在外周免疫细胞，特别是T淋巴细胞不起作用的小鼠模型中没有发挥直接的再生功能。因此，我们认为MSC发挥其作用需要外周免疫系统，这独立于中枢神经系统的直接影响。
Remyelination is the natural repair mechanism in demyelinating disorders such as multiple sclerosis (MS) and it was proposed that it might protect from axonal loss. For unknown reasons, remyelination is often incomplete or fails in MS lesions and therapeutic treatments to enhance remyelination are not available. Recently, the transplantation of exogenous mesenchymal stem cells (MSC) has emerged as a promising tool to enhance repair processes. This included the animal model experimental autoimmune encephalomyelitis (EAE), a commonly used model for the autoimmune mechanisms of MS. However, in EAE it is not clear if the beneficial effect of MSC derives from a direct influence on brain resident cells or if this is an indirect phenomenon via modulation of the peripheral immune system. The aim of this study was to determine potential regenerative functions of MSC in the toxic cuprizone model of demyelination that allows studying direct effects on de- and remyelination without the influence of the peripheral immune system. MSC from three different species (human, murine, canine) were transplanted either intraventricularly into the cerebrospinal fluid or directly into the lesion of the corpus callosum at two time points: at the onset of oligodendrocyte progenitor cell (OPC) proliferation or the peak of OPC proliferation during cuprizone induced demyelination. Our results show that MSC did not exert any regenerative effects after cuprizone induced demyelination and oligodendrocyte loss. During remyelination, MSC did not influence the dynamics of OPC proliferation and myelin formation. In conclusion, MSC did not exert direct regenerative functions in a mouse model where peripheral immune cells and especially T lymphocytes do not play a role. We thus suggest that the peripheral immune system is required for MSC to exert their effects and this is independent from a direct influence of the central nervous system.