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，我们研究了Apaf 1和Bc 1-XL双敲除胚胎中神经元的发育。在双基因敲除小鼠中，神经元的积累与Apaf 1单基因敲除胚胎中一样。然而，神经干细胞分化成成熟的神经元是正常的Apaf 1单和双敲除小鼠。接下来，我们证明了BMP 2驱动神经干细胞分化为星形胶质细胞。实际上，BMP 2通过诱导抑制性HLH因子并由此抑制有利于神经分化的bHLH转录因子来抑制干细胞向神经元的分化。在神经/脊柱的再生疗法中，移植的干细胞倾向于分化成星形细胞是一个严重的问题。另一个问题是移植的干细胞在宿主体内的生存能力差。由于Apaf 1缺陷的干细胞对各种凋亡刺激具有抗性，同时显示出正常的神经元分化，因此我们的结果可能有助于通过驱动凋亡抗性干细胞任意分化为神经元来开发新的神经再生疗法

项目成果

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。

Guo Z他: "Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis"Cancer Res. 61・23. 8395-8400 (2001)

郭Z等人：“视网膜母细胞瘤肿瘤抑制因子的失活在胚胎发生过程中诱导凋亡蛋白酶激活因子1依赖性和非依赖性凋亡途径”Cancer Res. 61・23 (2001)。

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”。

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

T.Takizawa 等人：“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.

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)。