誘導多能干細胞及其產(chǎn)生的功能細胞移植被認為是治療遺傳病、器官損傷以及帕金森等退行性疾病的重要手段，但目前該領域的瓶頸是對此缺乏分子機理認識,。最近,，我國科學家發(fā)現(xiàn)了一種新細胞生物學機制,，有望推動誘導多能干細胞技術(shù)更快地應用到疾病治療中,。
中科院廣州生物醫(yī)藥與健康研究院研究員裴端卿、鄭輝的團隊完成的這一研究成果26日在線發(fā)表于國際學術(shù)期刊《自然·細胞生物學》,。
據(jù)介紹,，誘導多能干細胞過程可以將人體內(nèi)的普通細胞“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)種類細胞的能力,，建立該技術(shù)的科學家憑此獲得了2012年度諾貝爾生理或醫(yī)學獎,。這一細胞水平的“返老還童”過程蘊藏著眾多生命奧秘，但目前人們對其知之甚少,。
我國科學家很早就認識到其潛在的意義與相關(guān)機制,。早在2010年，裴端卿團隊就發(fā)現(xiàn),，細胞“逆轉(zhuǎn)”過程是由間充質(zhì)細胞狀態(tài)轉(zhuǎn)變到上皮細胞狀態(tài)來驅(qū)動的,。在進一步的研究中，裴端卿,、鄭輝團隊通過優(yōu)化轉(zhuǎn)化因子導入的順序,，發(fā)現(xiàn)在間充質(zhì)轉(zhuǎn)變到上皮細胞狀態(tài)前還存在一個上皮向間充質(zhì)細胞狀態(tài)轉(zhuǎn)換過程，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)與中國傳統(tǒng)陰陽太極理念較一致,。我們進一步推論，間充質(zhì)細胞狀態(tài)與上皮細胞狀態(tài)之間的多次相互轉(zhuǎn)換機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。
科學家表示,，間充質(zhì)細胞狀態(tài)和上皮細胞狀態(tài)之間的順序性相互轉(zhuǎn)變這一發(fā)現(xiàn),，將可以進一步提高體細胞重編程為誘導多能干細胞過程。這一新細胞生物學機制有望推動誘導多能干細胞研究的理論和實踐突破,，為干細胞治療帕金森等退行性疾病開辟新途徑,。（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.
