成体细胞逆分化为干细胞只需改变四个基因
生物谷报道：干细胞生物学研究中最大的一个问题就是克隆过程如何能让成熟细胞恢复年幼，使它们回到胚胎细胞状态。理想状态就是找到一种方法将成年细胞之间转化成胚胎干细胞，并且无需先创造出一个胚胎。在近期举行的国际干细胞研究协会的会议上，来自东京大学的Shinya Yamanaka报告说，只需要促进四个基因的活性就能将小鼠皮肤细胞变成与胚胎干细胞状态非常相似的细胞。
干细胞（生物谷配图）
Yamanaka和同事想知道使胚胎干细胞拥有它们的独特性质的因子是否还能重新编排成年细胞，使其行为像胚胎干细胞。他们确定出在小鼠胚胎干细胞中表达的24个基因并利用病毒载体将这些基因的额外拷贝引入从小鼠尾巴顶部获得的皮肤细胞中。当他们将24个基因的额外拷贝都插入细胞后发现，吸收了这些基因的小部分细胞确实表现出了胚胎干细胞的特征。但是只引入一个基因不能引发这种转变。
通过排除法，研究组将候选基因删减到了4个：当将它们同时引入小鼠尾巴细胞中时，能够产生出类似胚胎干细胞的克隆。这四个基因中的三个基因是之前已经认识的，它们是Oct4、Sox2和从c-Myc。这些基因都是早期胚胎和胚胎干细胞中的关键基因。Yamanaka目前还未给第四个基因命名，但他透露说这个基因是一种目前尚未知晓的在胚胎干细胞中起关键作用的转录因子。在此之前，他们小组还发现了干细胞自我更新关键因子Nanog.
引入这四个基因的细胞似乎具备了从胚胎衍生的胚胎干细胞的所有关键特征。它们在培养皿中形成了几种类型的组织并在给免疫缺陷小鼠注射后形成了肿瘤。
Yamanaka表示，研究组尚未尝试将该技术用于人类细胞。因为人类和小鼠胚胎发育的差异，有可能利用另外一套基因来编排人类细胞。如果在不久的将来人们也能够通过改变个别几个基因就将人类的成熟细胞逆转为胚胎干细胞而无需创造出胚胎，那么干细胞在人类疾病治疗上的应用将会具有更广泛的应用前景。而且，这种技术比之前黄禹锡欺骗公众的干细胞克隆技术更加先进，更规避了可能的伦理谴责。
相关报道：
Nature: 美国科学家发现控制胚胎干细胞“永存”的7种基因
P4诱导id蛋白抑制胚胎干细胞的分化维持自我更新
英文报道：
One of the biggest questions in stem cell biology is how the cloning process manages to turn back the clock of mature cells, resetting them to their embryonic potential. Ideally, researchers would like to find a way to convert adult cells directly into to embryonic stem (ES) cells--without having to create an embryo at all. At a meeting of the International Society for Stem Cell Research here, Shinya Yamanaka of Kyoto University in Japan reported that boosting the activity of just four genes can apparently turn mouse skin cells into cells that closely resemble ES cells.
Yamanaka and his colleagues wondered whether the factors that give ES cells their unique properties might also be able to reprogram adult cells to behave like ES cells. They identified 24 genes that are specifically expressed in mouse ES cells and used viral vectors to introduce extra copies of the genes into skin cells taken from mouse tail tips. When they inserted extra copies of all 24 genes, they found that a small percentage of cells that took up the genes did indeed seem to take on characteristics of ES cells. But no single gene introduced alone was able to manage the transformation.
Through a process of elimination, the team whittled down the candidates to a suite of just four genes that, when introduced together into the tail-tip cells, could produce colonies of ES-like cells. As Yamanaka described, three of the four factors are old friends: Oct4, Sox2, and c-Myc are all key genes in both early embryos and ES cells. Yamanaka did not name the fourth gene, but he said it is a transcription factor that until now has not been recognized as playing a major role in ES cells.
The ES-like cells the group produced with the four introduced genes seemed to have almost all the key properties of ES cells derived from embryos. They formed several kinds of tissue in the culture dish and produced tumors called teratomas when they were injected under the skin of immune-compromised mice--both classic characteristics of ES cells.
Yamanaka says his group has not yet tried the technique with human cells. Because of differences in human and mouse embryo development, he says, it's possible that a different set of genes would be required to reprogram human cells.
Other researchers at the meeting were impressed. "It's huge," says Kevin Eggan of Harvard University, who also works on cell reprogramming. Still, he notes that the process is not yet very efficient; the four introduced genes managed to reprogram just 1 out of 1000 cells that received them. That suggests that the four genes are perhaps not the whole story, and that another factor could improve the efficiency of the process. "But this is the litmus test" for finding the genes that are essential for reprogramming, he says.
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