对于干细胞来说，时间是关键。为了维持分化的全能性，需要一种分子机制，将细胞维持在自我更新的状态直到这些干细胞被邻近组织需要。最近，洛克菲勒大学研究员Elaine Fuchs发现，皮肤中一种叫做Tcf3的蛋白是此分子机制关键成分，既维持干细胞的未分化状态，又在关键时刻刺激干细胞分化。
成年人皮肤中的毛囊隆突部（hair follicle bulge）是干细胞来源之一，毛囊隆突干细胞能够帮助毛发新生、修复受损表皮，在进行新一轮毛囊周期（hair follicle cycle）或者修复损伤之前，一直处于静止状态。隆突周围环绕着不同的细胞。今年Cell杂志一篇文章指出Tcf3是干细胞分化总调节者之一，首先表达于胚胎表皮中未确定分化方向的细胞（uncommitted cells），然后在命运的安排下，特异表达于预计发育为成熟毛囊隆突的毛囊区域。
“我们早已知道Tcf3表达于隆突中，” Fuchs说，但是我们没有预料到Tcf3在胚胎祖细胞中也存在，并且抑制这些细胞向表皮、毛囊和皮脂腺方向分化。
Tcf3是DNA结合蛋白Tcf/Lef家族成员，被视为β-连锁蛋白(β- catenin蛋白)的搭档。在皮肤干细胞中，分子信号抑制β- catenin。细胞接收Wnt蛋白信号后，避免了β-catenin降解，使其能够稳定地进入细胞核，与转录因子复合物TCF/LEF结合，开启干细胞分化相关基因。Fuchs及其同事想知道的是，在没有Wnt信号的条件下，Tcf3在干细胞中是否也能发挥功能。
“我希望获得一种可以控制Tcf3的表达系统，以监控在Wnt信号缺失情况下Tcf3的效果，”文章第一作者、Fuchs实验室博士后Hoang Nguyen说，“我研制了一种小鼠模型，可以随时重新激活Tcf3。当出生后增生扩散的皮肤细胞表达Tcf3表达时，向上皮、皮脂腺和毛囊的分化被抑制了。”
Nguyen利用基因芯片将隆突干细胞、胚胎上皮和Tcf3被重新激活的细胞，三种细胞的基因图谱（gene profiles）进行对比。Tcf3在小鼠细胞中重新启动后，许多基因的活性受到影响，具有隆突细胞和未分化的胚胎表皮细胞的基因表达特征。
“我们先前的研究证实Wnt信号途径在干细胞的激活和维持中扮演重要角色。Hoang的发现揭示了Tcf3在Wnt信号缺失的情况下对于干细胞也有重要作用，” Fuchs说：“我们在皮肤干细胞研究中的发现为胚胎干细胞等其它类型的干细胞研究提供了参考。”
英文原文：
A master repressor protein, Tcf3, holds stem cells back until the time is right
For stem cells, timing is key: To maintain their versatility they rely on a molecular mechanism that keeps the cells in a state of self-renewal until they are needed by adjacent tissue. Now, new research by Rockefeller University Elaine Fuchs reveals that in skin, the Tcf3 protein is a critical component of this mechanism, where it functions both to keep stem cells from differentiating and to motivate them to a specific lineage when the time is right.
In adult skin, a reservoir of stem cells is thought to reside in a region of each hair follicle known as the bulge, where the cells are used to provide new hair growth and to repair epidermal wounds. Stem cells in the follicle bulge remain at rest until needed in a new hair follicle cycle or for wound repair. But the bulge is surrounded by differentiated cells, and so how the stem cells maintain their undifferentiated state has remained a mystery. In research published this year in Cell, researchers have fingered Tcf3 as a master regulator of differentiation, showing that it is expressed first in the uncommitted cells of embryonic skin and then, as fates are specified, it becomes restricted to the region of the hair follicle that will become the bulge of the mature hair follicles.
We have known for a long time that Tcf3 is expressed in the bulge, where the multipotent stem cells of the skin reside,?says Fuchs. But we didn't anticipate that Tcf3 would also be expressed in embryonic progenitors and act as a global repressor of all three of the differentiated states ?epidermis, hair follicle and sebaceous gland ?afforded to these cells.
Tcf3 is part of the Tcf/Lef family of DNA binding proteins that are best known as partners for the protein beta-catenin. In skin stem cells, molecular signals continually repress beta-catenin, until the cell receives a Wnt protein signal. When this happens, beta-catenin becomes stabilized, allowing it to associate with Tcf/Lef proteins and turn on genes in the stem cell that activate it to divide and start down a path of differentiation. Fuchs and her colleagues wondered whether Tcf3 may have a function in stem cells even during times when the cells were not exposed to Wnt signaling.
I wanted a system where I could control the expression of Tcf3 in order to monitor its effects in the absence of Wnt signaling,?says Hoang Nguyen, a postdoc in Fuchs lab and first author of the paper. I created a mouse in which I could re-activate Tcf3 at any time. When Tcf3 is turned on in proliferating skin cells postnatally, differentiation of the epidermis, sebaceous gland and hair follicles is blocked.?
Using microarray analysis, Nguyen next compared the gene profiles of the bulge stem cells, embryonic skin and the cells that had re-activated Tcf3. The group of genes that were affected when I turned Tcf3 back on in mice were also characteristic of the natural pattern of gene expression seen in bulge cells and in undifferentiated embryonic skin,"says Nguyen.
Our prior studies revealed a role for Wnt signaling in stem cell activation and maintenance. Hoang抯 findings have now uncovered a role for Tcf3 in stem cells even when Wnt signaling is absent,"says Fuchs. It is becoming increasingly clear that Tcf/Lef proteins and Wnt signaling play very important roles in stem cell biology, and our studies on skin stem cells should provide insights relevant to other stem cel
