最新《自然》直击两大研究热点

　　

生物通报道：来自霍德华休斯医学院，洛克菲勒大学哺乳动物细胞与发育生物学实验室，瑞士联邦理工学院（Swiss Federal Institute of Technology ETH Zurich，简称ETH，生物通注）的研究人员将皮肤自我更新过程与一种miRNA联系了起来，并且发现这种miRNA能通过抑制p63导致上皮内层的干细胞离开并迁移到皮肤表面时，迅速转换为末端分化的细胞。这无论对于miRNA研究还是干细胞研究都意义重点。这一研究成果公布在3月13日的《Nature》杂志上。

领导这一研究的是洛克菲勒大学的女性研究员Elaine Fuchs博士，其一直致力于皮肤和毛发的研究，在2004年她与其同事从小鼠皮肤的毛囊中分离到促进毛发生长的干细胞，进而通过寻找干细胞特有的蛋白质和基因确定了它的身份，如果人类与小鼠的情况相似，那么就可能利用相同的方法提取干细胞。这种细胞可能被培养起来并移植到秃头或伤口，并且希望它能适当地形成新的皮肤或头发，但是这一研究成果发表在《Cell》上，受到了这一领域的广泛关注。

事隔三年，随着干细胞研究越来越受到重视，Fuchs博士等人又在之前研究的基础上发现了一种小分子RNA：miR-203与皮肤中干细胞特性的关系。

微小RNA(microRNA，简称miRNA)是生物体内源长度约为20－23个核苷酸的非编码小RNA，通过与靶mRNA的互补配对而在转录后水平上对基因的表达进行负调控，导致mRNA的降解或翻译抑制。到目前为止，已报道有几千种miRNA存在于动物、植物、真菌等多细胞真核生物中，进化上高度保守。

近年来这种小分子已经成为许多科学家们的“宠儿”，在这一研究中，研究人员发现miR-203这种miRNA表达十分奇怪：当胚胎发育时，miR-203的表达在两天内迅速增长。在胚胎发育的第十三天时，几乎还检测不到，但两天之后就成为皮肤中表达最丰富的miRNA。

为了了解这种miRNA的具体作用，研究人员进一步确定了miR-203在哪里表达，已经发现有microRNA是心脏和肌肉组织特异的，还有一些几乎完全是在大脑中表达。然而，miR-203仅仅在非常特异的皮肤中表达：复层上皮组织（ stratified epithelial tissue）。更精确地说仅仅在这类皮肤的外层表达。此外，在人类、斑马鱼、鸡等等动物中，换句话说在脊椎动物中，microRNA-203的表达模式都相似，而这些脊椎动物早在4亿年前就发生进化分离了。

通过一系列的实验，Fuchs博士等人确定microRNA-203可以阻断p63蛋白的转译，从而导致上皮内层的干细胞离开并迁移到皮肤表面时，迅速转换为末端分化的细胞。也就是说miR-203并不在上皮干细胞中表达，而是在细胞进行分化时产生的。它抑制细胞的“干性”（stemness），通过抑制p63（已知调控皮肤中干细胞维护的一种蛋白）的生成来完成功能。
（生物通：万纹）

原文摘要：
Nature 452, 225-229 (13 March 2008) |
doi:10.1038/nature06642; Received 9 August 2007; Accepted 8 January 2008; Published online 2 March 2008
A skin microRNA promotes differentiation by repressing 'stemness'
『Abstract』

附：
Elaine Fuchs, Ph.D.

Elaine Fuchs is fascinated by skin and hair—two very distinct structures that develop from the same skin stem cell. By unraveling the biology of skin stem cells, she hopes to answer a question that has intrigued her for more than two decades: How does a skin stem cell decide to become skin or hair? Understanding skin stem cells' normal behavior is also helping Fuchs learn what happens when their growth goes awry. Her studies have already uncovered the genetic basis of blistering skin diseases and clues to the way skin cancers and inflammatory skin disorders develop.

Her research may also hold clues for deciphering the extraordinary characteristics of stem cells that enable them to develop into distinct tissues and organs. "While there is much promise for stem cells in revolutionizing medicine, we must first learn more about stem cells before we can know whether this might be possible," she contends.

Unlike most other adult stem cells, skin stem cells can be easily grown in the laboratory. Studies by Fuchs have shown that multiple signaling pathways, including the Wnt and BMP pathways, influence how stem cells are coaxed to develop into hair follicles. Together, positive Wnt signals and antagonistic BMP signals lead to activation of a transcription factor, which induces the formation of a hair follicle bud. In the absence of these signals, stem cells develop into skin epidermis. This line of research may eventually lead to new ways to restore or inhibit hair growth. By exploring how stem cells are activated to proliferate and differentiate, Fuchs' work is having an impact on understanding how defective stem cells can cause cancers.

Fuchs believes strongly that research scientists do not operate in a vacuum but rather have an "obligation to a larger community of scientists, government, and the public," she said. "I feel that the best way I can teach and mentor is to lead by example—through a love and enthusiasm for my science, a dedication to research and an awareness of the medical and ethical implications involved, and by setting up the right environment conducive to learning."