2011年11月30日，干細(xì)胞權(quán)威雜志Stem Cells在線發(fā)表了一篇論文表明,，樂(lè)衛(wèi)東等研究胚胎干細(xì)胞移植治療的成瘤性獲突破,。胚胎干細(xì)胞具有體外培養(yǎng)無(wú)限增殖、自我更新和多向分化的特性,。無(wú)論在體外還是體內(nèi)環(huán)境,，胚胎干細(xì)胞都能被誘導(dǎo)分化為幾乎所有的細(xì)胞類型。因此,，胚胎干細(xì)胞是細(xì)胞移植治療中非常重要的細(xì)胞來(lái)源,。但是，胚胎干細(xì)胞治療存在一個(gè)非常大的問(wèn)題,，即成瘤風(fēng)險(xiǎn),，移植細(xì)胞中存在的未分化的胚胎干細(xì)胞會(huì)在被移植體內(nèi)成瘤。因此除去移植細(xì)胞中存在的未分化的胚胎干細(xì)胞是國(guó)內(nèi)外胚胎干細(xì)胞治療研究中要解決的首要問(wèn)題,。
健康科學(xué)研究所神經(jīng)基因組博士研究生王頤等在樂(lè)衛(wèi)東研究員的指導(dǎo)下,，通過(guò)建立小鼠胚胎干細(xì)胞的基因開關(guān)(GeneSwitch)系統(tǒng)，發(fā)現(xiàn)可控的誘導(dǎo)表達(dá)caspase-1不影響胚胎干細(xì)胞的分化潛能,，并且能特異殺死移植細(xì)胞中存在的未分化的胚胎干細(xì)胞,，而已經(jīng)分化為神經(jīng)前體的細(xì)胞不受影響。進(jìn)一步的研究發(fā)現(xiàn),，將分化的和未分化的細(xì)胞移植到小鼠的腦內(nèi),，通過(guò)誘導(dǎo)過(guò)量表達(dá)caspase-1，可以完全去除成腦內(nèi)的成瘤問(wèn)題,。該研究在國(guó)際上首次詳細(xì)闡明了通過(guò)量表達(dá)自殺基因caspase-1殺死未分化的胚胎干細(xì)胞解決了移植中的成瘤風(fēng)險(xiǎn)的問(wèn)題,。本研究為臨床胚胎干細(xì)胞治療疾病減少成瘤風(fēng)險(xiǎn)提供了非常重要理論基礎(chǔ),，對(duì)帕金森病等神經(jīng)退行性疾病的細(xì)胞治療以及其他以胚胎干細(xì)胞為基礎(chǔ)的細(xì)胞治療提供了重要實(shí)驗(yàn)基礎(chǔ), 具有非常重要的應(yīng)用價(jià)值和前景。
該工作得到了國(guó)家自然科學(xué)基金委,、科技部973項(xiàng)目,、交通大學(xué)優(yōu)博基金等項(xiàng)目的資助。(生物谷 Bioon.com)
doi:10.1002/stem.1000
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Mifepristone Inducible Caspase-1 Expression in Mouse Embryonic Stem Cells Eliminates Tumor Formation but Spares Differentiated Cells in vitro and in vivo
Yi Wang, Dehua Yang,Lin Song, Ting Li, Juan Yang, Xiaojie Zhang, Weidong Le
Embryonic 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.
