Transplantation of differentiated and genetically modified human embryonic stem cells in Parkinsonian rats via a hydrogel-biomatrix enriched in GDNF, VEGF, reelin and tenascin-C

通过富含 GDNF、VEGF、reelin 和 tenascin-C 的水凝胶生物基质在帕金森病大鼠中移植分化和转基因的人类胚胎干细胞

• 批准号: 59962383
• 负责人: Dr. Gunnar Hargus, Ph.D.
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/59962383?language=en
• 关键词: Transplantation; differentiated; genetically; modified; human

Parkinson’s disease is associated with a degeneration of dopamine neurons in the substantia nigra causing severe problems in motor initiation and coordination in patients. Since the medical treatment often looses its efficacy over time and may also cause debilitating side effects, this study aims to generate a population of dopaminergic cells derived from human embryonic stem cells that is suitable for replacing degenerated neurons after transplantation. Since the transplantation of highly differentiated and specialized neurons in the brain is known to be associated with problems regarding survival and integration into the host tissue, these cells should be implanted into a rat model of Parkinson’s disease in three-dimensional hydrogel-scaffolds. These scaffolds will contain the growth factors GDNF and VEGF that support cell survival and maintain the dopamine phenotype. Furthermore, these scaffolds will include the matrix proteins reelin and tenascin-C that should mediate cellular integrity due to cell-matrix interaction and should drive the migration of implanted cells inside the host tissue. Additionally, these scaffolds are aimed to attract endogenous, host-derived neuroblasts to support the process of stem cell-mediated regeneration in Parkinsonian rats. Finally, human embryonic stem cells will be genetically modified and FACS-sorted in order to purify the neural cell population and thus to remove residual tumorigenic potential of these cells.

帕金森氏病与黑质中多巴胺神经元的变性有关，导致患者在运动启动和协调方面出现严重问题。由于药物治疗往往随着时间的推移而失去疗效，也可能导致衰弱的副作用，本研究的目的是产生一个人口的多巴胺能细胞来源于人类胚胎干细胞，适合移植后取代退化的神经元。由于已知脑中高度分化和特化的神经元的移植与关于存活和整合到宿主组织中的问题相关，因此这些细胞应该以三维水凝胶支架植入帕金森病大鼠模型中。这些支架将包含支持细胞存活和维持多巴胺表型的生长因子GDNF和VEGF。此外，这些支架将包括由于细胞-基质相互作用而应该介导细胞完整性的基质蛋白质reelin和腱生蛋白-C，并且应该驱动植入细胞在宿主组织内的迁移。此外，这些支架旨在吸引内源性宿主来源的神经母细胞，以支持帕金森病大鼠中干细胞介导的再生过程。最后，将对人胚胎干细胞进行遗传修饰和FACS分选，以纯化神经细胞群，从而去除这些细胞的残余致瘤潜力。