兩個(gè)人血小板源性生長(zhǎng)因子受體β(platelet-derived growth factor receptor beta,，PDGFRβ)分子(用黃色和洋紅色表示)與一個(gè)二聚體PDGF-B(青色和綠色表示)形成復(fù)合物的的色帶圖,，圖片來(lái)自維基共享資源。
來(lái)自美國(guó)塔夫斯大學(xué)的一個(gè)研究小組鑒定出重編程皮膚細(xì)胞(reprogrammed skin cell)DNA上存在的控制基因表達(dá)瞬時(shí)變化的表觀遺傳標(biāo)記(epigenetic signature),。這些標(biāo)記能夠用來(lái)預(yù)測(cè)重編程皮膚細(xì)胞或者說(shuō)誘導(dǎo)性多功能干細(xì)胞(induced pluripotent stem cells, iPSCs)中一種起著愈合傷口作用的蛋白的表達(dá),。科學(xué)家一直希望利用對(duì)病人皮膚細(xì)胞進(jìn)行重編程而產(chǎn)生的iPSC細(xì)胞,，而不是人胚胎干細(xì)胞,，來(lái)開(kāi)發(fā)出一種實(shí)現(xiàn)個(gè)人化組織再生的策略。理解如何控制這種蛋白的表達(dá)讓我們朝這一目標(biāo)更走近一步,。相關(guān)研究結(jié)果于2012年2月17日在線發(fā)表在Journal of Cell Science期刊上,。
當(dāng)對(duì)皮膚細(xì)胞進(jìn)行重編程之后，它們對(duì)自身的細(xì)胞屬性進(jìn)行重新校準(zhǔn),，因?yàn)樗鼈儷@得干細(xì)胞屬性,，并能夠經(jīng)過(guò)誘導(dǎo)而再次變成皮膚細(xì)胞。為了使得這些“誘導(dǎo)性”干細(xì)胞能夠用于人類(lèi)治療,，如組織再生和個(gè)人化傷口愈合療法等等,，研究人員需要理解當(dāng)對(duì)它們進(jìn)行重編程之后，它們?nèi)绾伪Ａ艋蛘呱踔粮纳扑鼈兊奶卣鳌?/p>
自從最初發(fā)現(xiàn)重編程技術(shù)以來(lái),，因?yàn)樵谥鼐幊踢^(guò)程期間存在著很多變數(shù),，科學(xué)家一直在奮力解決這種細(xì)胞不可預(yù)測(cè)性,。就像這項(xiàng)研究開(kāi)展的那樣，對(duì)特異性的表觀遺傳標(biāo)記進(jìn)行分門(mén)別類(lèi)將允許研究人員找出一種方法來(lái)產(chǎn)生用于組織修復(fù)的細(xì)胞,，并且這種細(xì)胞擁有最完美的性質(zhì)同時(shí)使得不想要的細(xì)胞異常最小化,。
研究人員利用重編程細(xì)胞來(lái)產(chǎn)生模擬體內(nèi)傷口修復(fù)環(huán)境的三維結(jié)締組織。為了驗(yàn)證血小板源性生長(zhǎng)因子受體β(platelet-derived growth factor receptor beta,，PDGFRβ)在組織再生和維護(hù)當(dāng)中所起的作用,，研究小組阻斷它在細(xì)胞內(nèi)的表達(dá)，從而損害細(xì)胞重建組織的能力,。
“我們確定組織成功再生與PDGFRβ表達(dá)相關(guān)聯(lián),。從理論上講，通過(guò)鑒定控制它表達(dá)的表觀遺傳標(biāo)記,，我們就能夠確定重編程細(xì)胞在整個(gè)發(fā)育過(guò)程中維持正常細(xì)胞特征的潛力” ,，論文第一作者Kyle Hewitt博士說(shuō)。他是塔夫斯大學(xué)塞克勒生物醫(yī)學(xué)科學(xué)研究生學(xué)院(Sackler School of Graduate Biomedical Sciences)細(xì)胞,、分子與發(fā)育生物學(xué)項(xiàng)目的一位研究生,，同時(shí)也是塔夫斯大學(xué)牙醫(yī)學(xué)院Garlick實(shí)驗(yàn)室的一名博士后研究員。
“利用重編程皮膚細(xì)胞產(chǎn)生病人特異性的細(xì)胞的能力可能允許人們開(kāi)發(fā)出改善的,、個(gè)人化的細(xì)胞療法用于傷口愈合,。這些重編程細(xì)胞可能潛在地作為一種工具用于藥物開(kāi)發(fā)、疾病建模和轉(zhuǎn)化醫(yī)學(xué),，同時(shí)不用擔(dān)心胚胎干細(xì)胞帶來(lái)的倫理爭(zhēng)議”,，論文通信作者Jonathan Garlick說(shuō)。(生物谷：towersimper編譯)
doi:10.1242/jcs.099192
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PDGFRβ Expression and Function in Fibroblasts Derived from Pluripotent Cells is Linked to DNA Demethylation
Kyle J. Hewitt, Yulia Shamis, Elana Knight, Avi Smith, Anna Maione, Addy Alt-Holland, Steven D. Sheridan, Stephen J. Haggarty and Jonathan A. Garlick
Platelet-derived growth factor receptor-beta (PDGFRβ) is required for the development of mesenchymal cell types, and plays a diverse role in the function of fibroblasts in tissue homeostasis and regeneration. In this study, we characterized the expression of PDGFRβ in fibroblasts derived from human embryonic stem cells and induced pluripotent stem cells, and showed that this expression is important for cellular functions including migration and extracellular matrix production and assembly in 3D self-assembled tissues. To determine potential regulatory regions predictive of expression of PDGFRβ following differentiation from ESC and iPSC, we analyzed the DNA methylation status of a region of the PDGFRβ promoter containing multiple CpG sites before and after differentiation. We demonstrated that this promoter region is extensively demethylated following differentiation, and represents a developmentally-regulated, differentially-methylated region linked to PDGFRβ expression. Understanding the epigenetic regulation of genes such as PDGFRβ, and identifying sites of active DNA demethylation, is essential for future applications of pluripotent stem cell-derived fibroblasts for regenerative medicine.
