Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells
Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells
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DOI：
10.1002/jnr.21652
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发表时间：
2008-07-01
影响因子：
4.2
通讯作者：
Takahashi, Jun
中科院分区：
文献类型：
--
作者：
Ideguchi, Makoto;Shinoyama, Mizuya;Takahashi, Jun
胚胎干细胞（ES）是一种很有前途的移植治疗供体来源，但在其临床应用之前必须解决几个问题。其中之一是宿主对同种异体移植物的免疫反应。在本文中，我们研究了宿主免疫反应对移植胚胎干细胞衍生神经前体细胞（NPCs）存活和分化的影响。我们通过基质细胞来源的诱导活性诱导小鼠胚胎干细胞，然后将其移植到小鼠大脑中，并给予或不给予免疫抑制剂环孢素A （CsA）。移植后2周和8周，在移植物周围观察到宿主源性小胶质细胞/巨噬细胞和淋巴细胞的积累。尽管在移植物体积上没有观察到显著差异，但CsA治疗降低了这种效应。这些数据表明，在胚胎干细胞衍生的npc异体移植物中发生免疫应答。然而，有趣的是，在免疫抑制的小鼠中，移植物中神经元与星形胶质细胞的比例更高。由于炎症细胞或免疫细胞产生各种细胞因子，我们在体外研究了IL-1 β、IL-6、ifn - γ和tnf - α对npc分化的影响。只有IL-6促进了胶质细胞的命运，这种作用可以通过添加IL-6中和抗体来逆转。这些结果表明，异体胚胎干细胞衍生的npc可以引起宿主大脑的免疫反应，但其强度不足以排斥移植物。更重要的是，活化的小胶质细胞和淋巴细胞在体内通过产生IL-6等细胞因子抑制移植物的神经元分化。(C) 2008 Wiley-Liss, Inc。
Embryonic stem (ES) cells are a promising donor source for transplantation therapy, but several problems must be solved before they can be clinically useful. One of these is the host immune reaction to allogeneic grafts. In this article, we examine the effect of the host immune reaction on survival and differentiation of grafted ES cell-derived neural precursor cells (NPCs). We induced NPCs from mouse ES cells by stromal cell-derived inducing activity and then transplanted them into mouse brains with or without administering the immunosuppressant cyclosporine A (CsA). Two and 8 weeks following transplantation, the accumulation of host-derived microglia/macrophages and lymphocytes was observed around the graft. This effect was reduced by CsA treatment, although no significant difference in graft volume was observed. These data suggest that an immune response occurs in allografts of ES cell-derived NPCs. Intriguingly, however, the ratio of neurons to astrocytes in the graft was higher in immunosuppressed mice. Because inflammatory or immune cells produce various cytokines, we examined the effect of IL-1 beta, IL-6, IFN-gamma, and TNF-alpha on the differentiation of NPCs in vitro. Only IL-6 promoted glial cell fate, and this effect could be reversed by the addition of an IL-6 neutralizing antibody. These results suggest that allogeneic ES cell-derived NPCs can cause an immune response by the host brain, but it is not strong enough to reject the graft. More important, activated microglia and lymphocytes can suppress neuronal differentiation of grafted NPCs in vivo by producing cytokines such as IL-6. (C) 2008 Wiley-Liss, Inc.