專題，PNAS:幽門螺桿菌可誘導(dǎo)體細(xì)胞恢復(fù)未分化細(xì)胞
更新時(shí)間：2012-11-18 瀏覽次數(shù)：6024
| 近期來自東京大學(xué)的一組研究人員卻發(fā)現(xiàn)了幽門螺桿菌具有令體細(xì)胞恢復(fù)未分化細(xì)胞，回到干細(xì)胞狀態(tài)的類似作用，引起了多方的關(guān)注。相關(guān)成果公布在《美國(guó)國(guó)家科學(xué)院院刊》（PNAS）雜志上 |
2012年的諾貝爾生理/醫(yī)學(xué)獎(jiǎng)?lì)C給了英國(guó)科學(xué)家約翰·戈登（John B. Gurdon）和日本科學(xué)家山中伸彌（Shinya Yamanaka）獲獎(jiǎng)，獲獎(jiǎng)理由是“成熟細(xì)胞可被重編程恢復(fù)多能性”。這種技術(shù)的關(guān)鍵就在于利用四種轉(zhuǎn)錄因子令體細(xì)胞重新獲得多能性。
經(jīng)過多年的研究，其誘導(dǎo)轉(zhuǎn)錄因子已經(jīng)被發(fā)現(xiàn)可以用多種成分來代替，有的研究人員將其減少為了三種，兩種，有的研究人員則利用蛋白來實(shí)現(xiàn)誘導(dǎo)作用，然而近期來自東京大學(xué)的一組研究人員卻發(fā)現(xiàn)了幽門螺桿菌具有令體細(xì)胞恢復(fù)未分化細(xì)胞，回到干細(xì)胞狀態(tài)的類似作用，引起了多方的關(guān)注。相關(guān)成果公布在《美國(guó)國(guó)家科學(xué)院院刊》（PNAS）雜志上。
幽門螺桿菌（Helicobacter pylori）是從胃黏膜中分離出來的一種彎曲樣桿菌?，F(xiàn)已確認(rèn)與慢性胃炎、消化性潰瘍病、低度惡性的胃鉆膜相關(guān)淋巴組織淋巴瘤和胃癌密切相關(guān)。
研究顯示幽門螺桿菌的慢性感染是胃黏膜腸化的主要原因，而且會(huì)受到腸特異性骶管相關(guān)同源異形盒 （CDX） 轉(zhuǎn)錄因子的異常誘導(dǎo)，其中CDX1和CDX2在這種腸化作用中扮演了重要角色。那么這些作用因子如何直接調(diào)控這種細(xì)胞，組織特異性開關(guān)的呢?
在這篇文章中，研究人員分析胃上皮細(xì)胞中被CDX1直接激活的基因，并從中找到了與重編程因子：SALL4 和 KLF5有關(guān)的干性特征，也就是說，當(dāng)幽門螺桿菌表達(dá)的蛋白進(jìn)入胃上皮細(xì)胞之后，CDX1就會(huì)激活這兩種基因，從而胃上皮細(xì)胞就會(huì)重編程成為一種類似干細(xì)胞，能發(fā)育成消化道各種細(xì)胞的干性細(xì)胞。
通過進(jìn)一步分析，研究人員還發(fā)現(xiàn)抑制SALL4 或KLF5的表達(dá)，就會(huì)導(dǎo)致這種特性消失，這從側(cè)面也證明了CDX1誘導(dǎo)的SALL4和KLF5能逆轉(zhuǎn)胃上皮細(xì)胞轉(zhuǎn)變成類似干細(xì)胞的祖細(xì)胞。
這也解釋了為什么長(zhǎng)期出現(xiàn)幽門螺桿菌感染造成的慢性胃炎，胃粘膜上就會(huì)出現(xiàn)腸道細(xì)胞，研究人員認(rèn)為這可能是由于重編程為類似干細(xì)胞狀態(tài)的細(xì)胞分裂出了腸道細(xì)胞。
這些研究均表明，幽門螺桿菌具有令體細(xì)胞恢復(fù)未分化細(xì)胞，回到干細(xì)胞狀態(tài)的類似作用，而且由于干細(xì)胞也具有癌變的性質(zhì)，因此這項(xiàng)研究也指出了此種感染與癌變的可能。
原文摘要：
Intestinal metaplasia of the stomach, a mucosal change characterized by the conversion of gastric epithelium into an intestinal phenotype, is a precancerous lesion from which intestinal-type gastric adenocarcinoma arises. Chronic infection with Helicobacter pylori is a major cause of gastric intestinal metaplasia, and aberrant induction by H. pylori of the intestine-specific caudal-related homeobox （CDX） transcription factors, CDX1 and CDX2, plays a key role in this metaplastic change. As such, a critical issue arises as to how these factors govern the cell- and tissue-type switching. In this study, we explored genes directly activated by CDX1 in gastric epithelial cells and identified stemness-associated reprogramming factors SALL4 and KLF5. Indeed, SALL4 and KLF5 were aberrantly expressed in the CDX1+ intestinal metaplasia of the stomach in both humans and mice. In cultured gastric epithelial cells, sustained expression of CDX1 gave rise to the induction of early intestinal-stemness markers, followed by the expression of intestinal-differentiation markers. Furthermore, the induction of these markers was suppressed by inhibiting either SALL4 or KLF5 expression, indicating that CDX1-induced SALL4 and KLF5 converted gastric epithelial cells into tissue stem-like progenitor cells, which then transdifferentiated into intestinal epithelial cells. Our study places the stemness-related reprogramming factors as critical components of CDX1-directed transcriptional circuitries that promote intestinal metaplasia. Requirement of a transit through dedifferentiated stem/progenitor-like cells, which share properties in common with cancer stem cells, may underlie predisposition of intestinal metaplasia to neoplastic transformation.