對于干細胞來說，時間是關鍵,。為了維持分化的全能性,，需要一種分子機制，將細胞維持在自我更新的狀態(tài)直到這些干細胞被鄰近組織需要,。最近,，洛克菲勒大學研究員Elaine Fuchs發(fā)現,，皮膚中一種叫做Tcf3的蛋白是此分子機制關鍵成分,，既維持干細胞的未分化狀態(tài)，又在關鍵時刻刺激干細胞分化,。
成年人皮膚中的毛囊隆突部（hair follicle bulge）是干細胞來源之一,，毛囊隆突干細胞能夠幫助毛發(fā)新生、修復受損表皮,，在進行新一輪毛囊周期（hair follicle cycle）或者修復損傷之前,，一直處于靜止狀態(tài)。隆突周圍環(huán)繞著不同的細胞,。今年Cell雜志一篇文章指出Tcf3是干細胞分化總調節(jié)者之一,，首先表達于胚胎表皮中未確定分化方向的細胞（uncommitted cells），然后在命運的安排下,，特異表達于預計發(fā)育為成熟毛囊隆突的毛囊區(qū)域,。
“我們早已知道Tcf3表達于隆突中，” Fuchs說,，但是我們沒有預料到Tcf3在胚胎祖細胞中也存在,，并且抑制這些細胞向表皮、毛囊和皮脂腺方向分化,。
Tcf3是DNA結合蛋白Tcf/Lef家族成員,，被視為β-連鎖蛋白(β- catenin蛋白)的搭檔,。在皮膚干細胞中，分子信號抑制β- catenin,。細胞接收Wnt蛋白信號后,，避免了β-catenin降解，使其能夠穩(wěn)定地進入細胞核,，與轉錄因子復合物TCF/LEF結合,，開啟干細胞分化相關基因。Fuchs及其同事想知道的是,，在沒有Wnt信號的條件下,，Tcf3在干細胞中是否也能發(fā)揮功能。
“我希望獲得一種可以控制Tcf3的表達系統,，以監(jiān)控在Wnt信號缺失情況下Tcf3的效果,，”文章第一作者、Fuchs實驗室博士后Hoang Nguyen說,，“我研制了一種小鼠模型,，可以隨時重新激活Tcf3。當出生后增生擴散的皮膚細胞表達Tcf3表達時,，向上皮,、皮脂腺和毛囊的分化被抑制了。”
Nguyen利用基因芯片將隆突干細胞,、胚胎上皮和Tcf3被重新激活的細胞,，三種細胞的基因圖譜（gene profiles）進行對比。Tcf3在小鼠細胞中重新啟動后,，許多基因的活性受到影響,，具有隆突細胞和未分化的胚胎表皮細胞的基因表達特征。
“我們先前的研究證實Wnt信號途徑在干細胞的激活和維持中扮演重要角色,。Hoang的發(fā)現揭示了Tcf3在Wnt信號缺失的情況下對于干細胞也有重要作用,，” Fuchs說：“我們在皮膚干細胞研究中的發(fā)現為胚胎干細胞等其它類型的干細胞研究提供了參考。”
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
