维甲酸联合GSK3和TGFβ受体抑制剂诱导人胚胎干细胞分化为后脑神经干细胞及其脊髓损伤治疗作用研究

项目名称： 维甲酸联合GSK3和TGFβ受体抑制剂诱导人胚胎干细胞分化为后脑神经干细胞及其脊髓损伤治疗作用研究

项目编号： No.81201442

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 谢杨

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 脊髓损伤(SCI)是一种严重的中枢神经系统创伤性疾病，致残率高，给人们生活和工作带来很大困扰。传统治疗手段如大剂量糖皮质激素、外科手术治疗等不能从根本上解决神经元的再生问题。神经干细胞（NSC）移植可有效改善受损脊髓的恢复，成为SCI治疗研究的焦点，但是NSC来源有限是该疗法发展的瓶颈。胚胎干细胞(ESC)具有多能性，并可无限增殖，体外诱导其向神经分化有望为神经干细胞移植提供稳定的细胞来源。项目组成员的前期研究首次发现联合GSK3和TGF beta信号通路的抑制剂（CHIR99021和SB431542）可将hESC诱导分化为具有中脑特性的NSC，且该NSC可在体外长期扩增并维持表型的稳定。我们假设在原有方案的基础上添加高浓度维甲酸，直接获得具有后脑特性的NSC。本课题拟采用该方案获得后脑特性的NSC，并研究其对脊髓损伤动物模型的治疗作用。该研究的开展将为SCI的神经干细胞治疗提供重要参考。

中文关键词： 胚胎干细胞；神经干细胞；分化；脊髓损伤；

英文摘要： Spinal cord injury (SCI) is a serious invasive disease of the central nervous system with high mutilation rate, and caused great distress to people's living and working. The conventional treatment, such as large doses of glucocorticoid hormones, surgical treatment cannot be a fundamental solution to the regeneration of neurons. Transplantation of neural stem cells (NSCs) can effectively improve the recovery of damaged spinal cord, having became the focus in the field of SCI therapy. However, the lack of transplantable NSCs has limited the development of this therapy. The embryonic stem cells (ESCs) can proliferate indefinitely and is expected to provide a valuable cell source of various diseases and injury. In our previous study, for the first time, we found that the joint induction of the inhibitors of GSK3 and TGF beta signaling pathway (CHIR99021, and SB431542) induced ESCs to differentiate into the NSCs with the characteristic midbrain identity. In addition, this NSCs can be amplified in long-term and maintain phenotypic stability in vitro. We assume that on the basis of the original protocol, we could directly obtain the NSCs with the hind brain characteristic by adding the high concentrations of retinoic acid during induction. This proposal intends to apply this protocol to induce ESCs differentiate into t

英文关键词： embryonic stem cells；neural stem cells；differentiation；spinal cord injury；