由麻省總醫(yī)院、哈佛干細(xì)胞研究所的研究人員領(lǐng)導(dǎo)的一個(gè)國(guó)際研究小組,，在新研究中繪制出了體細(xì)胞重編程為誘導(dǎo)多能干(iPS)細(xì)胞的分子線路圖,，相關(guān)論文發(fā)表在12月21日的《細(xì)胞》（Cell）雜志上,。
人類胚胎干（ES）細(xì)胞具有在體外大量增殖和分化為多種細(xì)胞的潛能，可為再生醫(yī)學(xué)的替代療法提供充足的細(xì)胞來(lái)源,。然而受到科學(xué),、倫理和監(jiān)管問(wèn)題的限制，使得ES細(xì)胞無(wú)法成為廣泛的治療移植材料,。
2006年,，日本京都大學(xué)山中伸彌（Shinya Yamanaka)團(tuán)隊(duì)通過(guò)向人體皮膚成纖維細(xì)胞中植入4個(gè)經(jīng)過(guò)重新編碼的基因Oct3/4、Sox2,、c-Myc,、Klf4 ，將成纖維細(xì)胞重新編程變成了全能性的類胚胎干細(xì)胞,。他們將這種重編程細(xì)胞命名為iPS細(xì)胞,。iPS細(xì)胞和ES細(xì)胞功能類似，且具有超越ES細(xì)胞的優(yōu)勢(shì),，iPS細(xì)胞可以由體細(xì)胞生成,，從而繞開(kāi)了ES細(xì)胞研究一直面臨的倫理和法律等諸多障礙。今年10月,，山中伸彌因在這一突破性的技術(shù)而獲得了諾貝爾生理/醫(yī)學(xué)獎(jiǎng),。
盡管這一技術(shù)使得成體細(xì)胞“返老返童”為干細(xì)胞變?yōu)榭赡埽@示出廣闊的醫(yī)學(xué)應(yīng)用前景,。世界各地各種iPS細(xì)胞研究開(kāi)展的熱火朝天,，然而將其真正應(yīng)用于臨床卻并不容易?？茖W(xué)人員長(zhǎng)期受困于iPS細(xì)胞誘導(dǎo)效率低下,、速度慢、組成復(fù)雜等障礙,。對(duì)于體細(xì)胞重編程過(guò)程的具體細(xì)節(jié)至今仍知之甚少,。
在這篇文章中，研究人員通過(guò)全基因組分析檢測(cè)了預(yù)備轉(zhuǎn)變?yōu)閕PS細(xì)胞的中間前體細(xì)胞。研究人員證實(shí)誘導(dǎo)多能性過(guò)程引起了兩次轉(zhuǎn)錄波,，第一波是由c-Myc/Klf4驅(qū)動(dòng),，第二波是由Oct4/Sox2/Klf4驅(qū)動(dòng)。難以發(fā)生重編程的細(xì)胞激活了第一波,，但卻無(wú)法啟動(dòng)第二轉(zhuǎn)錄波,，提高4個(gè)因子的表達(dá)則可以解決這一問(wèn)題。此外,，研究人員發(fā)現(xiàn)在第一波后逐漸形成了一些雙價(jià)基因（Bivalent genes）,，而在第二波后細(xì)胞獲得穩(wěn)定的多能性之時(shí)細(xì)胞才發(fā)生DNA甲基化改變。通過(guò)這一綜合性的分析,，研究人員還確定了在重編程過(guò)程中充當(dāng)路障的基因,，以及細(xì)胞進(jìn)一步富集從而使之更易于形成iPSCs的表面標(biāo)記物。
這些研究數(shù)據(jù)為我們提供了關(guān)于細(xì)胞重編程固有分子事件的特征,、順序及分子機(jī)制的詳細(xì)的見(jiàn)解,。這些認(rèn)識(shí)對(duì)于提高重編程的效率，及其未來(lái)的治療應(yīng)用具有非常重要的意義,。(生物谷Bioon.com)
DOI:10.1016/j.cell.2012.11.039
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A Molecular Roadmap of Reprogramming Somatic Cells into iPS Cells
Jose M. Polo, Endre Anderssen, Ryan M. Walsh, Benjamin A. Schwarz, Christian M. Nefzger, Sue Mei Lim, Marti Borkent, Effie Apostolou, Sara Alaei, Jennifer Cloutier, Ori Bar-Nur, Sihem Cheloufi, Matthias Stadtfeld, Maria Eugenia Figueroa, Daisy Robinton, Sridaran Natesan, Ari Melnick, Jinfang Zhu, Sridhar Ramaswamy, Konrad Hochedlinger
Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, whereas changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming.
