據(jù)物理學(xué)家組織網(wǎng)4月2日（北京時(shí)間）報(bào)道，美國(guó)維克森林浸禮會(huì)醫(yī)學(xué)中心再生醫(yī)學(xué)研究所科學(xué)家通過(guò)基因工程修改了一種干細(xì)胞,，使其表達(dá)一種常見(jiàn)皰疹病毒的蛋白質(zhì),，從而能躲避免疫系統(tǒng)攻擊，大大提高了存活率,。受傷或病變組織因此能爭(zhēng)取更多時(shí)間發(fā)揮自身愈合能力,，得以治愈。相關(guān)論文發(fā)表在最近出版的《公共科學(xué)圖書(shū)館·綜合》上,。
“基本上我們是幫干細(xì)胞‘隱身’,，讓體內(nèi)天然‘殺手’T細(xì)胞和免疫系統(tǒng)對(duì)它們‘視而不見(jiàn)’，這樣它們就能生存下來(lái)并促進(jìn)身體康復(fù),。”論文高級(jí)作者,、研究所再生醫(yī)學(xué)教授格雷卡·阿爾梅達(dá)-普拉達(dá)解釋說(shuō)，“干細(xì)胞天生具有幫助調(diào)節(jié)免疫反應(yīng)的能力,。如果能增加它們的存活率，理論上就能作為一種治療措施,，降低炎癥反應(yīng),，幫助器官移植病人避免排斥反應(yīng)等。”
研究使用的是間充質(zhì)干細(xì)胞（MSCs）,，存在于骨髓,、外周血與臍帶血、胎兒肝臟和肺等組織中,。這些細(xì)胞在免疫調(diào)節(jié),、營(yíng)養(yǎng)等方面具有特殊性，能優(yōu)先遷移到受傷的身體組織,，促進(jìn)創(chuàng)傷愈合,。但MSCs也像其他細(xì)胞一樣,，容易被身體的免疫系統(tǒng)攻擊殺死。
常見(jiàn)病毒是人類(lèi)巨細(xì)胞病毒（HCMV）,，是皰疹病毒家族的成員之一,，能在人體長(zhǎng)期潛伏卻不使人發(fā)病。“我們想利用這種病毒躲避免疫系統(tǒng)的能力,。”阿爾梅達(dá)-普拉達(dá)說(shuō),，“方法是修改細(xì)胞讓它們產(chǎn)生和HCMV相同的蛋白質(zhì)，這樣它們就不會(huì)被殺死,。”
研究人員從人類(lèi)胎兒肝臟組織中提取了MSCs,，通過(guò)基因工程讓它們也能產(chǎn)生HMCV病毒表達(dá)的特殊蛋白質(zhì)。在此過(guò)程中,，他們識(shí)別出了能最有效地增加細(xì)胞存活率的蛋白質(zhì)——US2蛋白,，并首次證明，US2蛋白過(guò)度表達(dá)會(huì)降低免疫系統(tǒng)對(duì)細(xì)胞的識(shí)別能力,，使其存活率提高大約59%,。
“研究顯示，基因修改后的細(xì)胞,，其存活率大大提高,。”阿爾梅達(dá)-普拉達(dá)說(shuō)，“下一步,，我們希望對(duì)它們?cè)谥委熌c道疾病,、外傷性腦損傷和人類(lèi)器官移植愈合方面的潛力進(jìn)行評(píng)估。”（生物谷Bioon.com）
DOI： 10.1371/journal.pone.0060461
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Mesenchymal Stem Cells Engineered to Inhibit Complement-Mediated Damage
Melisa A. Soland, et al
Mesenchymal stem cells (MSC) preferentially migrate to damaged tissues and, due to their immunomodulatory and trophic properties, contribute to tissue repair. Although MSC express molecules, such as membrane cofactor protein (CD46), complement decay-accelerating factor (CD55), and protectin (CD59), which confer protection from complement-mediated lysis, MSC are recruited and activated by anaphylatoxins after transplantation, potentially causing MSC death and limiting therapeutic benefit. We have previously demonstrated that transduction of MSC with a retrovirus encoding HCMV-US proteins resulted in higher levels of MSC engraftment due to decreased HLA-I expression. Here, we investigate whether engineering MSC to express US2 (MSC-US2), US3 (MSC-US3), US6 (MSC-US6), or US11 (MSC-US11) HCMV proteins can alter complement recognition, thereby better protecting MSC from complement attack and lysis. HCMV-US proteins increased MSC CD59 expression at different levels as determined by flow cytometric evaluation of the median fluorescence intensity ratio (MFI). A significant increase in CD59 expression was seen in MSC-US2, MSC-US3, and MSC-US6, but not in MSC-US11. Only MSC-US2 displayed increased expression of CD46, while US2 and US3 proteins were both able to augment the percentage of MSC expressing this molecule. Regardless of the HCMV protein expressed, none changed CD55 MFI; however, expression of US6, US11, and US2 each increased the percentage of MSC that were positive for this molecule. Because US2 protein was the most efficient in up-regulating all three complement regulatory proteins, we used a functional complement-mediated cytotoxicity assay to investigate whether MSC-US2 were protected from complement-mediated lysis. We demonstrated that over-expression of the US2 protein reduced complement lysis by 59.10±12.89% when compared to untransduced MSC. This is the first report, to our knowledge, describing a role of HCMV-US proteins in complement evasion, and our data shows that over-expression of US2 protein on MSC could serve as a strategy to protect these cells from complement lysis.
