Trauma-associated inflammatory response impairs embryonic stem cell survival and integration after implantation into injured rat brain
Trauma-associated inflammatory response impairs embryonic stem cell survival and integration after implantation into injured rat brain
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DOI：
10.1089/neu.2006.0180
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发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Schaefer, Ute
中科院分区：
文献类型：
--
作者：
Molcanyi, Marek;Riess, Peter;Schaefer, Ute
多能胚胎干细胞在植入帕金森病和脑缺血的实验模型后显示出存活并分化为成熟的神经元细胞。胚胎干细胞移植也被提议作为脑外伤的潜在治疗方法，脑外伤的特点是由于原发性损伤和继发性后遗症导致多种细胞类型大量损失。液体冲击损伤后 72 小时，将绿色荧光蛋白 (GFP) 转染的小鼠胚胎干细胞植入雄性 Sprague-Dawley 大鼠的同侧或对侧皮层中。在植入后第5天或第7周处死动物。使用常规和荧光双标记免疫组织化学检查脑切片。植入五天后，在植入部位检测到沿神经元通路部分分化的 GFP 阳性细胞簇。然而，7周后，只发现了少数GFP阳性细胞，表明在此期间干细胞大量损失。我们首次证明观察到的细胞损失是通过活化的巨噬细胞对植入细胞的吞噬作用介导的。植入前 3 天诱发的脑损伤激活了其他免疫特权组织的炎症潜力。随后的细胞植入伴随着反应性星形胶质细胞增生、小胶质细胞的激活以及巨噬细胞大量侵入移植部位，即使移植物被放置在远离创伤性病变的对侧健康半球中。我们的结果表明，显着的创伤后炎症反应会损害植入干细胞的存活和整合，并且在之前的移植研究设计中通常没有考虑到。
Pluripotent embryonic stem cells were shown to survive and differentiate into mature neuronal cells after implantation in experimental models of Parkinson disease and cerebral ischemia. Embryonic stem cell transplantation has also been proposed as a potential therapy for cerebral trauma, characteristic of massive loss of multiple cell types due to primary insult and secondary sequelae. Green fluorescent protein (GFP)-transfected murine embryonic stem cells were implanted into the ipsi or contralateral cortex of male Sprague-Dawley rats 72 h after fluid-percussion injury. Animals were sacrificed at day 5 or week 7 postimplantation. Brain sections were examined using conventional and fluorescent double-labelling immunohistochemistry. Five days after implantation, clusters of GFP-positive cells undergoing partial differentiation along neuronal pathway, were detected at the implantation site. However, after 7 weeks, only a few GFP-positive cells were found, indicating an extensive loss of stem cells during this time period. For the first time, we proved the observed cell loss to be mediated via phagocytosis of implanted cells by activated macrophages. Cerebral trauma, induced 3 days prior to implantation, has activated the inflammatory potential of otherwise immunologically privileged tissue. Subsequent cell implantation was accompanied by reactive astrogliosis, activation of microglia, as well as a massive invasion of macrophages into transplantation sites even if the grafts were placed into contralateral healthy hemispheres, remote from the traumatic lesion. Our results demonstrate a significant post-traumatic inflammatory response, which impairs survival and integration of implanted stem cells and has generally not been taken into account in designs of previous transplantation studies.