Study of differentiation of apoptosis-resistant nerve stem cells and their application to neuroregeneration

抗凋亡神经干细胞的分化研究及其在神经再生中的应用

• 批准号: 13558093
• 负责人: YOSHIDA Hiroki
• 金额: $ 9.02万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13558093/
• 关键词: apoptosis; neuron; differentiation; mitochondria; regeneration; 神経幹細胞; Apaf1

First we examined the development of neurons in Apaf1- and Bc1-XL-doubly knockout embryos. In the doubly-knockout mice, there was accumulation of neurons just as in Apaf1-single knockout embryos. However, differentiation of nerve stem cells into mature neurons was normal in both Apaf1-single and doubly knockout mice. Next we demonstrated BMP2drives the differentiation f nerve stem cells into astrocytes. Practically, BMP2 suppresses the differentiation of stem cells into neurons by the induction of inhibitory HLH factors and the resultant suppression of bHLH transcription factors that favor nerve differentiation. In regeneration of therapies of nerve/spine, it is a serious problem that transplanted stem cells tend to differentiate into astorocytes. Another problem will be the poor viability of transplanted stem cells in the host. Since Apaf1-deficient stem cells are resistant to various apoptotic stimuli while showing normal differentiation into neurons, our results may shed light to the development of novel neuroregenerative therapies by driving the differentiation of apoptosis-resistant stem cells arbitrarily into neurons

首先，我们检查了APAF1和BC1-XL-敲除胚胎中神经元的发展。在双重敲除小鼠中，就像在APAF1单敲敲门胚胎中一样，神经元积聚。然而，在APAF1单个和双重敲除小鼠中，神经干细胞为成熟神经元分化为成熟神经元。接下来，我们证明BMP2将分化神经干细胞置于星形胶质细胞中。实际上，BMP2通过诱导抑制性HLH因子以及对有利于神经分化的BHLH转录因子的抑制抑制干细胞向神经元的分化。在神经/脊柱疗法的再生中，移植的干细胞倾向于分化为astorocytes是一个严重的问题。另一个问题将是宿主中移植干细胞的生存力差。由于APAF1缺陷的干细胞在表现为神经元正常分化的同时对各种凋亡刺激具有抗性，因此我们的结果可能通过推动抗凋亡耐药性干细胞的分化为神经元的分化来使新的神经加续性疗法的发展降低。

项目成果

N.Joza, et al.: "Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death"Nature. 410. 549-554 (2001)

N.Joza 等人：“线粒体凋亡诱导因子在程序性细胞死亡中的重要作用”。

Takayanagi, H. 他: "Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts"Dev Cell. 3・6. 889-901 (2002)

Takayanagi, H. 等人：“转录因子 NFATc1 (NFAT2) 的诱导和激活在破骨细胞的终末分化中整合 RANKL 信号传导”Dev Cell 3・6。

Z. Guo, et al.: "Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease activating factor-1 dependent and independent apoptotic pathways during embryogenesis"Cancer research. 61. 8395-8400 (2001)

Z.Guo 等人：“视网膜母细胞瘤肿瘤抑制因子的失活会在胚胎发生过程中诱导凋亡蛋白酶激活因子 1 依赖和独立的凋亡途径”癌症研究。

Z.Guo, et al.: "Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis"Cancer research. 61. 8395-8400 (2001)

Z.Guo 等人：“视网膜母细胞瘤肿瘤抑制因子的失活会在胚胎发生过程中诱导凋亡蛋白酶激活因子 1 依赖和独立的凋亡途径”癌症研究。

Takizawa, T., 他: "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain"Dev Cell. 1・6. 749-758 (2001)

Takizawa, T., et al.：“DNA 甲基化是胎儿大脑中星形胶质细胞分化的关键细胞内在决定因素”Dev Cell 1・6 (2001)。