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过量表达caspase-1可消除胚胎干细胞移植成瘤风险

2011/12/14 来源:《干细胞》
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本研究在国际上首次详细阐明了通过过量表达自杀基因caspase-1杀死未分化的胚胎干细胞解决了移植中的成瘤风险的问题,对帕金森病等神经退行性疾病的细胞治疗以及其他以胚胎干细胞为基础的细胞治疗提供了重要实验基础,具有非常重要的应用价值和前景。

胚胎干细胞具有体外培养无限增殖、自我更新和多向分化的特性。无论在体外还是体内环境,胚胎干细胞都能被诱导分化为几乎所有的细胞类型。因此,胚胎干细胞是细胞移植治疗中非常重要的细胞来源。但是,胚胎干细胞治疗存在一个非常大的问题,即成瘤风险,移植细胞中存在的未分化的胚胎干细胞会在被移植体内成瘤。因此除去移植细胞中存在的未分化的胚胎干细胞是国内外胚胎干细胞治疗研究中要解决的首要问题。

中科院上海生命科学研究院健康科学研究所神经基因组博士研究生王颐等在乐卫东研究员的指导下,通过建立小鼠胚胎干细胞的基因开关(GeneSwitch)系统,发现可控的诱导表达caspase-1不影响胚胎干细胞的分化潜能,并且能特异杀死移植细胞中存在的未分化的胚胎干细胞,而已经分化为神经前体的细胞不受影响。进一步的研究发现,将分化的和未分化的细胞移植到小鼠的脑内,通过诱导过量表达caspase-1,可以完全去除成脑内的成瘤问题。

该研究在国际上首次详细阐明了通过过量表达自杀基因caspase-1杀死未分化的胚胎干细胞解决了移植中的成瘤风险的问题。本研究为临床胚胎干细胞治疗疾病减少成瘤风险提供了非常重要理论基础,对帕金森病等神经退行性疾病的细胞治疗以及其他以胚胎干细胞为基础的细胞治疗提供了重要实验基础,具有非常重要的应用价值和前景。

该研究成果于11月30日在线发表于干细胞权威杂志Stem Cells(Mifepristone Inducible Caspase-1 Expression in Mouse Embryonic Stem Cells Eliminates Tumor Formation but Spares Differentiated Cells in vitro and in vivo)。该工作得到了国家自然科学基金委、科技部973项目、交通大学优博基金等项目的资助。


胚胎干细胞移植治疗成瘤性研究获突破 参考文献

Mifepristone Inducible Caspase‐1 Expression in Mouse Embryonic Stem Cells Eliminates Tumor Formation but Spares Differentiated Cells in vitro and in vivo

Wang, Yi; Yang, Dehua; Song, Lin; Li, Ting; Yang, Juan; Zhang, Xiaojie; Le, Weidong

Keywords:Caspase;embryonic stem cell;neural differentiation;transplantation;tumor cell purgingAbstractEmbryonic stem (ES) cell‐based therapy is a promising treatment for neurodegenerative diseases. But there is always a risk of tumor formation generating from contamination of undifferentiated ES cells. To reduce the risk and improve ES cell‐based therapy, we have established a novel strategy by which we can selectively eliminate tumor cells derived from undifferentiated ES cells but spare differentiated cells. In the present study we generated a caspase‐1‐ES cell line transfected with a mifepristone regulated caspase‐1 expression system. Mifepristone induced caspase‐1 overexpression both in differentiated and undifferentiated caspase‐1‐ES cells. All the undifferentiated caspase‐1‐ES cells were induced to death after mifepristone treatment. Tumors derived from undifferentiated caspase‐1‐ES cells were eliminated following 3 weeks mifepristone treatment in vivo. However, differentiated caspase‐1‐ES cells survived well under the condition of mifepristone‐induced caspase‐1 overexpression. To examine in vivo the influence of mifepristone treatment on differentiated cells, undifferentiated caspase‐1‐ES cells were transplanted into nude mice brains. After 8 weeks' mifepristone treatment we could not detect any tumor cells in the caspase‐1‐ES cells grafts in the brains of mice. However, we found donor dopamine neurons survived in the recipient brains. These data demonstrate that mifepristone induced caspase‐1 overexpression in ES cells can eliminate the potential tumor formation meanwhile spares the differentiated cells in the host brains. These results suggest that this novel ES cell‐based therapy can be used in Parkinson's disease and other related disorders without the risk of tumor formation.

文献链接:http://onlinelibrary.wiley.com/doi/10.1002/stem.1000/abstract

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