Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.
Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.
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DOI：
10.1371/journal.pone.0157620
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Walsh CM
中科院分区：
文献类型：
--
作者：
Plaisted WC;Zavala A;Hingco E;Tran H;Coleman R;Lane TE;Loring JF;Walsh CM
我们最近描述了在人类脱髓鞘疾病多发性硬化症的病毒模型中移植来自人胚胎干细胞（hESC）的神经前体细胞（NPC）后，与神经炎症和髓鞘再生抑制相关的持续临床恢复。该研究中使用的hNPC是通过一种新的直接分化方法（直接分化，DD-NPC）获得的，与通过常规方法获得的hNPC相比，该方法导致独特的基因表达模式。由于人类NPC的治疗潜力可能因来源和培养方法的不同而存在很大差异，我们想确定使用常规方法分化的NPC是否在神经炎症脱髓鞘条件下同样有效地改善临床结果。对于目前的研究，我们利用从人诱导多能细胞系通过胚状体中间阶段（EB-NPC）分化的hNPC。将EB-NPCs椎管内移植到感染嗜神经性小鼠肝炎病毒（JHMV）JHM株的小鼠中，导致中枢神经系统中CD 4 + T细胞的积累减少，这伴随着注射部位脱髓鞘减少。抑制神经炎症和髓鞘再生与集中在外周神经系统内的CD 4 + FOXP 3+调节性T细胞（TCFs）的短暂增加相关。然而，与我们早期的研究相比，病理学改善是适度的，并没有导致显着的临床恢复。我们的结论是，NPC的基因签名是至关重要的，他们的有效性，在这个模型中的病毒引起的神经系统疾病。这些比较将有助于了解哪些因素对持续的临床改善至关重要。
We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs) that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs). Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement.