Immature and neurally differentiated mouse embryonic stem cells do not express a functional Fas/Fas ligand system
Immature and neurally differentiated mouse embryonic stem cells do not express a functional Fas/Fas ligand system
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DOI：
10.1634/stemcells.2006-0745
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Sonntag, Kai-Christian
中科院分区：
文献类型：
--
作者：
Brunlid, Gabriella;Pruszak, Jan;Sonntag, Kai-Christian
多能胚胎干细胞（ES）发育成功能性细胞或组织的潜力为许多疾病（包括神经退行性疾病）的新疗法的开发提供了机会。移植细胞的存活通常需要全身性免疫抑制，然而，这严重损害宿主免疫系统，导致临床移植的并发症。因此，最佳疗法将是诱导对供体细胞的特异性耐受，同时以其他方式保留功能性免疫应答。Fas配体（FasL）在活化的淋巴细胞以及包括中枢神经系统在内的“免疫特权”部位的细胞中表达。其受体Fas在各种免疫反应性细胞类型上表达，如活化的自然杀伤细胞和T细胞、单核细胞和多态性单核细胞，其可在与FasL相互作用后发生凋亡。为了使移植细胞耐受宿主细胞免疫反应，我们基因工程小鼠ES细胞表达大鼠FasL（rFasL）。分析表达rFasL的ES细胞在体外神经分化过程中和移植到大鼠脑中后的存活情况，而不进行进一步的免疫抑制。尽管对照转染的HEK-293 T细胞表达功能性rFasL，但未成熟和分化的小鼠ES细胞不表达重组rFasL表面蛋白。此外，没有证据表明ES细胞或体外分化后的神经细胞上有功能性内源性Fas和FasL表达。此外，在没有免疫抑制剂环孢霉素A的情况下，植入的rFasL工程ES细胞不能在大鼠脑中存活。我们的研究结果表明，未成熟和分化的小鼠ES细胞不表达功能性Fas/FasL系统。
The potential of pluripotent embryonic stem ( ES) cells to develop into functional cells or tissue provides an opportunity in the development of new therapies for many diseases including neurodegenerative disorders. The survival of implanted cells usually requires systemic immunosuppression, however, which severely compromises the host immune system, leading to complications in clinical transplantation. An optimal therapy would therefore be the induction of specific tolerance to the donor cells, while otherwise preserving functional immune responses. Fas ligand ( FasL) is expressed in activated lymphocytes as well as cells in "immune-privileged" sites including the central nervous system. Its receptor, Fas, is expressed on various immune-reactive cell types, such as activated natural killer and T cells, monocytes, and polymorphic mononucleocytes, which can undergo apoptosis upon interaction with FasL. To render transplanted cells tolerant to host cellular immune responses, we genetically engineered mouse ES cells to express rat FasL ( rFasL). The rFasL-expressing ES cells were analyzed for survival during in vitro neurodifferentiation and after transplantation to the rat brain without further immunosuppression. Although control transfected HEK-293T cells expressed functional rFasL, immature and differentiated mouse ES cells did not express the recombinant rFasL surface protein. Furthermore, there was no evidence for functional endogenous Fas and FasL expression on either ES cells or on neural cells after in vitro differentiation. Moreover, implanted rFasL-engineered ES cells did not survive in the rat brains in the absence of the immunosuppressive agent cyclosporine A. Our results indicate that immature and differentiated mouse ES cells do not express a functional Fas/FasL system.