圍繞腸壁的環(huán)形肌一個(gè)眾所周知的功能就是產(chǎn)生腸蠕動(dòng),，促進(jìn)食物的推進(jìn),。而在果蠅體內(nèi),，它還有一個(gè)極為重要的功能,，那就是維持腸上皮干細(xì)胞的自我更新,。這項(xiàng)干細(xì)胞研究的最新發(fā)現(xiàn)由北京生命科學(xué)研究所襲榮文博士帶領(lǐng)的課題組完成，并在線刊登在9月21日的《自然》（Nature）雜志上,。
襲榮文利用果蠅作為實(shí)驗(yàn)?zāi)Ｐ?，在分子和?xì)胞水平上證明了干細(xì)胞的微環(huán)境對(duì)干細(xì)胞的調(diào)控作用。“環(huán)形肌構(gòu)成了腸上皮干細(xì)胞的微環(huán)境,。”他發(fā)現(xiàn),，環(huán)形肌分泌的信號(hào)因子維持著腸上皮干細(xì)胞的存在并控制著它的活性。
他說(shuō),，這種控制著果蠅腸上皮干細(xì)胞自我更新的叫做Wnt信號(hào)因子,，能夠穿越一薄層由細(xì)胞外基質(zhì)組成的基底膜，然后到達(dá)干細(xì)胞的表面,，結(jié)合并激活干細(xì)胞膜上的受體,，隨之激活一系列下游成員和轉(zhuǎn)錄因子，從而在轉(zhuǎn)錄水平上調(diào)控基因的表達(dá)和干細(xì)胞的自我更新,。抑制Wnt信號(hào)通路上任何一個(gè)環(huán)節(jié)都會(huì)導(dǎo)致干細(xì)胞的分化和丟失,。相反，Wnt信號(hào)通路的過(guò)量激活可以直接導(dǎo)致干細(xì)胞的積聚和腫瘤的發(fā)生,。Wnt信號(hào)通路在哺乳動(dòng)物和人身上也被認(rèn)為是控制腸上皮干細(xì)胞自我更新的一個(gè)主要機(jī)制,。
此項(xiàng)發(fā)現(xiàn)證明了以果蠅作為一個(gè)模式來(lái)解析腸道干細(xì)胞調(diào)控機(jī)制的可行性。果蠅在遺傳學(xué)上的優(yōu)勢(shì)將有助于進(jìn)一步解析腸道干細(xì)胞的調(diào)節(jié)機(jī)制及腸道腫瘤等疾病的發(fā)生機(jī)制。另外,，該研究也揭示了一個(gè)嶄新的干細(xì)胞微環(huán)境結(jié)構(gòu),。環(huán)形肌作為微環(huán)境細(xì)胞并不與腸上皮干細(xì)胞直接接觸，而是被一層基底膜隔開(kāi),。干細(xì)胞散布在基底膜上,，并沒(méi)有局部區(qū)域的聚集。研究干細(xì)胞的調(diào)控機(jī)制,，對(duì)理解腫瘤等疾病的發(fā)生進(jìn)而有針對(duì)性地制定干預(yù)措施,，以期達(dá)到治愈目的具有重要意義。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature,，doi:10.1038/nature07329，Guonan Lin,，Rongwen Xi
Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells
Guonan Lin1,2, Na Xu2 & Rongwen Xi2
1 Graduate program, Peking union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
2 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
In the Drosophila midgut, multipotent intestinal stem cells (ISCs) that are scattered along the epithelial basement membrane maintain tissue homeostasis by their ability to steadily produce daughters that differentiate into either enterocytes or enteroendocrine cells, depending on the levels of Notch activity1, 2, 3. However, the mechanisms controlling ISC self-renewal remain elusive. Here we show that a canonical Wnt signalling pathway controls ISC self-renewal. The ligand Wingless (Wg) is specifically expressed in the circular muscles next to ISCs, separated by a thin layer of basement membrane. Reduced function of wg causes ISC quiescence and differentiation, whereas wg overexpression produces excessive ISC-like cells that express high levels of the Notch ligand, Delta. Clonal analysis shows that the main downstream components of the Wg pathway, including Frizzled, Dishevelled and Armadillo, are autonomously required for ISC self-renewal. Furthermore, epistatic analysis suggests that Notch acts downstream of the Wg pathway and a hierarchy of Wg/Notch signalling pathways controls the balance between self-renewal and differentiation of ISCs. These data suggest that the underlying circular muscle constitutes the ISC niche, which produce Wg signals that act directly on ISCs to promote ISC self-renewal. This study demonstrates markedly conserved mechanisms regulating ISCs from Drosophila to mammals. The identification of the Drosophila ISC niche and the principal self-renewal signal will facilitate further understanding of intestinal homeostasis control and tumorigenesis.
