誘導(dǎo)多能干細(xì)胞及其產(chǎn)生的功能細(xì)胞移植被認(rèn)為是治療遺傳病、器官損傷以及帕金森等退行性疾病的重要手段,，但目前該領(lǐng)域的瓶頸是對(duì)此缺乏分子機(jī)理認(rèn)識(shí),。最近，我國(guó)科學(xué)家發(fā)現(xiàn)了一種新細(xì)胞生物學(xué)機(jī)制,，有望推動(dòng)誘導(dǎo)多能干細(xì)胞技術(shù)更快地應(yīng)用到疾病治療中,。
中科院廣州生物醫(yī)藥與健康研究院研究員裴端卿、鄭輝的團(tuán)隊(duì)完成的這一研究成果26日在線(xiàn)發(fā)表于國(guó)際學(xué)術(shù)期刊《自然·細(xì)胞生物學(xué)》,。
據(jù)介紹,，誘導(dǎo)多能干細(xì)胞過(guò)程可以將人體內(nèi)的普通細(xì)胞“逆轉(zhuǎn)”回到早期胚胎發(fā)育狀態(tài)，從而重新獲得分化成為體內(nèi)絕大多數(shù)種類(lèi)細(xì)胞的能力,，建立該技術(shù)的科學(xué)家憑此獲得了2012年度諾貝爾生理或醫(yī)學(xué)獎(jiǎng),。這一細(xì)胞水平的“返老還童”過(guò)程蘊(yùn)藏著眾多生命奧秘，但目前人們對(duì)其知之甚少,。
我國(guó)科學(xué)家很早就認(rèn)識(shí)到其潛在的意義與相關(guān)機(jī)制,。早在2010年，裴端卿團(tuán)隊(duì)就發(fā)現(xiàn),，細(xì)胞“逆轉(zhuǎn)”過(guò)程是由間充質(zhì)細(xì)胞狀態(tài)轉(zhuǎn)變到上皮細(xì)胞狀態(tài)來(lái)驅(qū)動(dòng)的,。在進(jìn)一步的研究中，裴端卿,、鄭輝團(tuán)隊(duì)通過(guò)優(yōu)化轉(zhuǎn)化因子導(dǎo)入的順序,，發(fā)現(xiàn)在間充質(zhì)轉(zhuǎn)變到上皮細(xì)胞狀態(tài)前還存在一個(gè)上皮向間充質(zhì)細(xì)胞狀態(tài)轉(zhuǎn)換過(guò)程，并證明這樣的多次轉(zhuǎn)換有利于提高重編程效率,。
“這一發(fā)現(xiàn)與中國(guó)傳統(tǒng)陰陽(yáng)太極理念較一致,。我們進(jìn)一步推論，間充質(zhì)細(xì)胞狀態(tài)與上皮細(xì)胞狀態(tài)之間的多次相互轉(zhuǎn)換機(jī)理具有較高的普遍性,，在其他系統(tǒng)或研究中也存在,。”裴端卿說(shuō)。
科學(xué)家表示,，間充質(zhì)細(xì)胞狀態(tài)和上皮細(xì)胞狀態(tài)之間的順序性相互轉(zhuǎn)變這一發(fā)現(xiàn),，將可以進(jìn)一步提高體細(xì)胞重編程為誘導(dǎo)多能干細(xì)胞過(guò)程。這一新細(xì)胞生物學(xué)機(jī)制有望推動(dòng)誘導(dǎo)多能干細(xì)胞研究的理論和實(shí)踐突破,，為干細(xì)胞治療帕金森等退行性疾病開(kāi)辟新途徑,。（生物谷Bioon.com）
Nature Cell Biology doi:10.1038/ncb2765
Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT–MET mechanism for optimal reprogramming
Xiaopeng Liu Hao Sun Jing Qi Linli Wang Songwei He Jing Liu Chengqian Feng Chunlan Chen Wen Li Yunqian Guo Dajiang Qin Guangjin Pan Jiekai Chen Duanqing Pei Hui Zheng
Present practices for reprogramming somatic cells to induced pluripotent stem cells involve simultaneous introduction of reprogramming factors. Here we report that a sequential introduction protocol (Oct4–Klf4 first, then c-Myc and finally Sox2) outperforms the simultaneous one. Surprisingly, the sequential protocol activates an early epithelial-to-mesenchymal transition (EMT) as indicated by the upregulation of Slug and N-cadherin followed by a delayed mesenchymal-to-epithelial transition (MET). An early EMT induced by 1.5-day TGF-β treatment enhances reprogramming with the simultaneous protocol, whereas 12-day treatment blocks reprogramming. Consistent results were obtained when the TGF-β antagonist Repsox was applied in the sequential protocol. These results reveal a time-sensitive role of individual factors for optimal reprogramming and a sequential EMT–MET mechanism at the start of reprogramming. Our studies provide a rationale for further optimizing reprogramming, and introduce the concept of a sequential EMT–MET mechanism for cell fate decision that should be investigated further in other systems, both in vitro and in vivo.
