四种因子赋予成熟细胞干细胞功能

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只需引入四种因子，研究人员成功使已分化的小鼠胚胎细胞或者成年小鼠细胞具有胚胎干细胞功能。研究详细结果将在新一期CELL杂志发表。

    这种被研究人员定义为“被诱导的多能性干细胞”（induced pluripotent stem cells，iPS）具有胚胎干细胞的经典的物理性质、生长方式和遗传学特征。多能性是指细胞能够分化为其它各种类型细胞的潜能。

    京都大学研究员Shinya Yamanaka说：“人类胚胎干细胞可以用于治疗帕金森氏症、脊髓损伤和糖尿病等多种疾病。然而目前实验和医疗还要考虑到利用人类胚胎的一些伦理问题和组织移植的排异反应。”假如能够直接采集到患者自身的多能性细胞，这些问题都迎刃而解了。

    Yamanaka说：“实验证明只需向培养纤维原细胞的培养基中添加几种因子即可以诱导产生多能性干细胞。”(纤维原细胞是在结缔组织中存在的一种结构纤维)。

    自然过程中胚胎干细胞来自于哺乳动物胚泡（blastocyst）细胞，受精卵首先进入胚泡阶段，然后胚泡发育进入胚胎发育阶段。早期研究已经证实，肌体其它组织的细胞也可以通过将其核质移植到卵母细胞或者通过与胚胎干细胞融合而实现“改编”（reprogrammed）为有干细胞分化潜能的细胞。Yamanaka说：“这些实验告诉我们未受精的卵子和胚胎干细胞可能包含一些成分，这些成分可以使已分化的细胞重新具有多能性。我们推测这些成分对维持胚胎干细胞的同一性至关重要，并且在诱导其它肌体细胞具有全能性的过程中扮演关键角色。”

    研究人员选择了先前已经证实的与维持早期胚胎和胚胎干细胞同一性有关的24种基因作为候选因素，寻找能够诱导肌体细胞转化为其它细胞类型的关键因素。研究结果发现其中的四种基因：Oct3/4、Sox2、c-Myc和Klf4可以使来自胚胎小鼠或者成年小鼠的不同的纤维原细胞保留胚胎干细胞正常的多能性。

    更进一步的实验发现，将这些iPS细胞移植到小鼠的皮下组织会导致肿瘤发生，这些肿瘤包括在哺乳动物胚胎中三种重要类型组织肿瘤。并且Yamanaka表示：“胚层”（germ layers）最终会发育成为完整的组织和器官。将iPS细胞注入胚泡，也能发现iPS细胞协助小鼠胚胎发育。

    “这些结果为研究控制多能性迈出了重要一步，有助于将患者体内细胞转化为多能性细胞提供思路。”因为这些研究结果有广泛的应用价值，干细胞专家谨慎地表示此项胚胎干细胞研究还有很大的发展空间。

    Yamanaka说：“我们仍然不知道的是，是否人类中的这四种基因可以诱导人类成体细胞（somatic cell）具有多能性。”  

    研究小组对干细胞将来的研究工作提出两点意见：一是强调c-Myc（一种在多种人类癌症中都出现的基因）也许不适合临床应用，并且治疗过程需要特定的培养环境；二是强调iPS细胞不一定具有胚胎干细胞所有功能。

英文原文：

With few factors, adult cells take on character of embryonic stem cells
With the introduction of just four factors, researchers have successfully induced differentiated cells taken from mouse embryos or adult mice to behave like embryonic stem cells. The researchers reported their findings in an immediate early publication of the journal Cell.

The cells--which the researchers designate \"induced pluripotent stem cells\" (iPS)--exhibit the physical, growth, and genetic characteristics typical of embryonic stem cells, they reported. \"luripotent\" refers to the ability to differentiate into most other cell types.

\"Human embryonic stem cells might be used to treat a host of diseases, such as Parkinson's disease, spinal cord injury, and diabetes,\" said Shinya Yamanaka of Kyoto University in Japan. \"However, there are ethical difficulties regarding the use of human embryos, as well as the problem of tissue rejection following transplantation into patients.\"

Those problems could be circumvented if pluripotent cells could be obtained directly from the patients' own cells.

\"We have demonstrated that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors,\" Yamanaka said. Fibroblasts make up structural fibers found in connective tissue.

Embryonic stem cells are derived from inner cells of the mammalian blastocyst, a ball of cells that develops after fertilization and goes on to form a developing embryo. Cells from other parts of the body can also be \"reprogrammed\" by transferring their nuclear contents into egg cell precursors called oocytes or by fusion with embryonic stem cells, earlier studies showed.

Those findings provided evidence that unfertilized eggs and embryonic stem cells contain factors that can confer pluripotency to differentiated cells, Yamanaka said.

\"We hypothesized that the factors that play important roles in the maintenance of embryonic stem cell identity also play pivotal roles in the induction of pluripotency\" in other body cells, he explained.

The researchers selected 24 genes--all previously found to play a role in early embryos and embryonic stem cell identity--as candidate factors that might give body cells the ability to become other cell types.

The researchers found that four of those factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells.

They further reported that transplantation of the iPS cells under the skin of mice resulted in tumors containing a variety of tissues representing the three primary types found in mammalian embryos. Those primary \"germ layers\" in embryos eventually give rise to all an animal's tissues and organs.

Following injection into blastocysts, iPS cells also contributed to mouse embryonic development.

\"The finding is an important step in controlling pluripotency, which may eventually allow the creation of pluripotent cells directly from somatic cells of patients,\" Yamanaka said.

While the findings could have wide applications, stem cell experts caution that the study of embryonic stem cells has much further to go.

\"We still do not know whether the four factors can generate pluripotent cells from human somatic cells,\" Yamanaka said. Use of c-Myc, a gene implicated in many human cancers, may not be suitable for clinical applications, they added, and the process may require specific culture environments. It also remains unclear whether iPS cells can do everything that embryonic stem cells can.