張金梅 楊遠(yuǎn)榮 熊建群 丁卓玲

·綜述·

應(yīng)用基因工程技術(shù)增強(qiáng)間充質(zhì)干細(xì)胞移植效果

張金梅 楊遠(yuǎn)榮 熊建群 丁卓玲

間充質(zhì)干細(xì)胞（MSCs）在再生醫(yī)學(xué)領(lǐng)域應(yīng)用前景無(wú)限。它取材較容易，無(wú)論是天然的還是通過(guò)細(xì)胞工程誘導(dǎo)獲得的均具有多向分化能力。成功的MSCs治療依賴于有效的細(xì)胞輸送和移植細(xì)胞的長(zhǎng)期存活，以便能長(zhǎng)久地在目標(biāo)位點(diǎn)更多地發(fā)揮效應(yīng)。在MSCs移植前應(yīng)用基因工程技術(shù)對(duì)其進(jìn)行修飾可取得這一效果。本文介紹了能提高移植MSCs的遷移能力、防止MSCs衰老和凋亡及提高M(jìn)SCs存活率的基因工程方法策略。

間質(zhì)干細(xì)胞； 基因工程； 細(xì)胞移植； 細(xì)胞運(yùn)動(dòng)； 細(xì)胞存活

人們對(duì)干細(xì)胞再生醫(yī)藥的興趣與日俱增，基因工程技術(shù)也被充分應(yīng)用于增強(qiáng)干細(xì)胞的治療效果。間充質(zhì)干細(xì)胞（Mesenchymal stem cells，MSCs）來(lái)源豐富，分化潛能大，在細(xì)胞治療方面極有應(yīng)用價(jià)值,但在實(shí)際應(yīng)用過(guò)程中遇到許多問(wèn)題，如怎樣將細(xì)胞有效的傳遞至目標(biāo)位點(diǎn)并維持較高的存活率。目前局部注射MSCs是最普遍的細(xì)胞移植方法，但局部注射有許多缺點(diǎn)，如大量的細(xì)胞沉積在精密的器官如大腦中會(huì)產(chǎn)生局部結(jié)構(gòu)壓力，導(dǎo)致微出血，引發(fā)炎癥反應(yīng)，從而增強(qiáng)宿主抗移植物反應(yīng)。血管內(nèi)注射是另一種有效的細(xì)胞移植方法，細(xì)胞隨著血液輸送到身體各個(gè)部位，包括大腦。靜脈注射將細(xì)胞分配到全身可能會(huì)減少到達(dá)損傷部位的細(xì)胞數(shù)量。動(dòng)脈注射靶向特定的身體部位。但移植細(xì)胞還是需要遷移一定的距離才能到達(dá)病變組織，細(xì)胞遷移能力弱會(huì)影響治療效果。這可通過(guò)基因工程方法來(lái)解決。MSCs長(zhǎng)期的體外培養(yǎng)會(huì)不可避免的衰老，從而導(dǎo)致增殖活性的喪失?；蚬こ碳夹g(shù)能增加干性相關(guān)基因的表達(dá)以維持干細(xì)胞的特性，甚至可以增加干細(xì)胞體外的增殖潛能。此外，傷口部位惡劣的微環(huán)境會(huì)對(duì)移植細(xì)胞產(chǎn)生不利的影響，如高水平的氧化應(yīng)激、局部缺氧以及促凋亡因子等都會(huì)加速移植細(xì)胞的消亡，這些都會(huì)影響治療效果。因此，還需要采取有效措施延長(zhǎng)移植細(xì)胞的存活時(shí)間。

一、增加MSCs遷移

SDF-1是細(xì)胞遷移過(guò)程中最強(qiáng)的趨化因子之一。在生理?xiàng)l件下，SDF-1由損傷組織合成，從受損部位釋放。在外層細(xì)胞膜上表達(dá)CXCR4受體[1]，這是趨化信號(hào)。不同的MSCs外層膜上的CXCR4基底蛋白不同。在體外培養(yǎng)中CXCR4會(huì)發(fā)生變化[1]。在低氧環(huán)境中MSCs中CXCR4的表達(dá)會(huì)大幅增加[2-3]，充分的刺激能引起了內(nèi)源性CXCR4基因的過(guò)表達(dá)[1,4]。采用基因工程增加MSCs中CXCR4基因的表達(dá)，導(dǎo)致高密度的表達(dá)CXCR4受體，能有效地增加MSCs向SDF-1的遷移[5-7]。

表達(dá)CXCR4的MSCs在腎臟移植中發(fā)揮有利的免疫調(diào)節(jié)作用[8]。CXCR4-遺傳改造的MSCs對(duì)早期的肝再生有積極地影響，增強(qiáng)移植肝的歸巢，促進(jìn)肝細(xì)胞的增殖[9]。

MSCs中CXCR4過(guò)表達(dá)能增強(qiáng)急性腎損傷模型的組織修復(fù)能力[10]。與對(duì)照組MSCs相比，CXCR4-MSCs歸巢到損傷部位的親和力更高，表現(xiàn)出有利的旁分泌作用。修飾了CXCR4的MSCs對(duì)傷口部位有較高的親和力，能加速傷口的愈合[11]。在大鼠缺血模型中，CXCR4-MSCs有更高的動(dòng)員能力和神經(jīng)保護(hù)作用[12]。除了SDF-1-CXCR4 信號(hào)軸的CXCR4修飾外，也采用過(guò)表達(dá)SDF-1的策略，Nakamura等[13]發(fā)現(xiàn)，SDF-1過(guò)表達(dá)DF-1/CXCR7的MSCs其體外遷移能力增強(qiáng)，SDF-1-MSCs被用于體內(nèi)傷口愈合實(shí)驗(yàn)?zāi)苊黠@縮小傷口面積。除了CXCR4與SDF-1結(jié)合外，CXC趨化因子受體7（CXCR7）也與SDF-1結(jié)合[14]。DF-1/CXCR7信號(hào)軸被用于MSCs遺傳修飾。Wang等[34]在腦缺血再灌注大鼠海馬模型中應(yīng)用CXCR7過(guò)表達(dá)的MSCs，證實(shí)了過(guò)表達(dá)的CXCR7受體促進(jìn)MSCs向SDF-1梯度遷移，與SDF-1/ CXCR4信號(hào)軸共同作用[15]。MSCs中過(guò)表達(dá)的CXCR7會(huì)導(dǎo)致他們向次級(jí)淋巴器官的遷移增加。CXCR7修飾的MSCs廣泛存在于這些器官中，可能會(huì)抑制移植物抗宿主病的免疫系統(tǒng)反應(yīng)，減少臨床癥狀[16]。

CXCR1也能提高M(jìn)SCs的遷移能力，CXCR1是IL-8的受體，在神經(jīng)膠質(zhì)瘤中表達(dá)和釋放[17]，被用于提高M(jìn)SCs對(duì)膠質(zhì)瘤的靶向能力[18]。研究表明CXCR1-MSCs對(duì)梗死的心肌有高親和力，移植CXCR1-MSCs的存活率也上升，為心肌損傷提供了一個(gè)新的治療方案[19]。MSCs的遷移能力還可通過(guò)對(duì)aquaporin-1（Aqp1）基因的修飾來(lái)調(diào)節(jié)，過(guò)表達(dá)的Aqp1會(huì)增加Aqp1-MSCs向損傷部位的遷移能力[20]。Aqp1是水通道分子，轉(zhuǎn)運(yùn)水分子穿過(guò)細(xì)胞膜。Aqp1與β-catenin相互作用是細(xì)胞遷移的重要調(diào)節(jié)者[21]。Nur77和Nurr1兩個(gè)細(xì)胞核受體也被用于提高M(jìn)SCs的遷移能力[22]。高表達(dá)Nur77和Nurr1是細(xì)胞遷移能力增強(qiáng)的特征[23-24]。病毒轉(zhuǎn)導(dǎo)ITGA-4足以增強(qiáng)MSCs的骨髓歸巢能力[25]。還有為增強(qiáng)血管壁的遷移對(duì)MSCs進(jìn)行雙重靶向修飾的研究，即同時(shí)應(yīng)用兩個(gè)mRNAs分別修飾PSGL-1和SLeX，使MSCs產(chǎn)生P-選擇素和E-選擇素功能性的配體，改善炎癥組織的MSCs歸巢[26-27]。

二、基因工程修飾MSCs以抗衰老

轉(zhuǎn)錄因子Oct4和Sox2參與維持胚胎干細(xì)胞的多能性和自我更新，早期用來(lái)重編程體細(xì)胞為誘導(dǎo)多能干細(xì)胞。Fan等[28]發(fā)現(xiàn)骨髓來(lái)源的MSCs同時(shí)過(guò)表達(dá)Sox2和Oct4基因，能改善增殖和分化潛能。在脂肪來(lái)源的MSCs中Sox2和Oct4的過(guò)表達(dá)有同樣的作用[29]。對(duì)骨髓MSCs進(jìn)行Sox2基因修飾更有效，能成功地保持未分化狀態(tài)。MSCs中Oct4基因的過(guò)表達(dá)導(dǎo)致其它干性基因如Sox2的表達(dá)增加[30]。Sox2和Oct4的過(guò)表達(dá)也可以通過(guò)同時(shí)采用leukemia inhibitory factor（LIF）和干細(xì)胞特異性miRNAs之一miR-302轉(zhuǎn)染來(lái)獲得[31]。MiR-302能誘導(dǎo)人脂肪MSCs增殖，抑制氧化劑誘導(dǎo)的細(xì)胞死亡[32]。

端粒酶逆轉(zhuǎn)錄酶（TERT）基因轉(zhuǎn)染是防止培養(yǎng)MSCs衰老的另一種策略。TERT是RNA依賴的DNA聚合酶，它合成和延伸末端DNA，維持干細(xì)胞的永生[33]。體外擴(kuò)增的MSCs缺乏TERT基因表達(dá)，為此，TERT基因工程成為逆轉(zhuǎn)MSCs衰老的方法。被TERT永生化的MSCs的細(xì)胞增殖能力增強(qiáng)，細(xì)胞周期相關(guān)的基因表達(dá)因子上升，防止了轉(zhuǎn)染MSCs的細(xì)胞周期阻滯[34]。蛋白酶體通路對(duì)維持細(xì)胞代謝有重要的作用，其功能失調(diào)會(huì)導(dǎo)致復(fù)制性衰老。用哺乳動(dòng)物蛋白酶體復(fù)合物（PSMB5）的β亞基轉(zhuǎn)染MSCs，也會(huì)抑制細(xì)胞衰老[35]。用小RNA干擾糖皮質(zhì)激素受體基因[36]和脂質(zhì)運(yùn)載蛋白-2基因的過(guò)表達(dá)保護(hù)缺氧條件下MSCs的多能性[37]，這都可防止MSCs的衰老。生長(zhǎng)因子基因的過(guò)表達(dá)可提高M(jìn)SCs的增殖能力，而某些生長(zhǎng)因子會(huì)嚴(yán)重傷害MSCs的治療特性。

三、提高M(jìn)SCs存活率

MSCs在缺氧時(shí)遷移到損傷部位，MSCs對(duì)惡劣的局部環(huán)境很敏感。治療細(xì)胞的存活率對(duì)損傷組織缺氧的傷口部位尤其重要，如心肌梗塞與腦卒中。為此，多種促存活的方法被采納，修飾MSCs以延長(zhǎng)其在靶器官中的存活率，給予足夠的時(shí)間以產(chǎn)生有益的影響。在體外培養(yǎng)的SDF-1β修飾的MSCs中，SDF-1β能增強(qiáng)細(xì)胞自噬，減少細(xì)胞凋亡，是促細(xì)胞存活因子[38]。低氧誘導(dǎo)因子（HIF-1α）是缺氧導(dǎo)致的細(xì)胞代謝變化的主要調(diào)節(jié)者[39]。HIF-1α調(diào)節(jié)一系列基因的活性包括血管生成、紅細(xì)胞生成、細(xì)胞增殖、分化及凋亡，使細(xì)胞適應(yīng)缺氧條件[40]。在小鼠后肢缺血模型[41]及大鼠心肌梗死模型[42]的試驗(yàn)中，HIF-1α基因工程MSCs取得好的效果。也可應(yīng)用MiRNA技術(shù)，修飾的MSCs過(guò)表達(dá)miR-210，miR-210對(duì)HIF-1α蛋白的活性有正反饋環(huán)調(diào)節(jié)作用，能促進(jìn)基因工程MSCs在缺氧條件下的存活率[43]。MSCs基因工程方法產(chǎn)生能抑制治療細(xì)胞凋亡信號(hào)的蛋白質(zhì)，這種蛋白質(zhì)提供由Bcl-2、E1A激活基因的細(xì)胞抑制因子（CREG）、激肽釋放酶（KLK1）、血管緊張素轉(zhuǎn)換酶2、精氨酸脫羧酶（ADC）、整合素連接激酶（ILK）、或蛋白激酶G1α介導(dǎo)的抗凋亡信號(hào)?？沟蛲鲂?yīng)可通過(guò)小發(fā)夾RNAs（shRNA）使基因表達(dá)沉默來(lái)實(shí)現(xiàn)。如用pre-miRNA-155-designed caspase8 shRNA轉(zhuǎn)染MSCs后，促凋亡因子caspase8基因停止表達(dá)[44]。保護(hù)MSCs不受惡血的不良影響是促移植細(xì)胞存活的一個(gè)重要方案[45]。采用MSCs細(xì)胞膜上的力生長(zhǎng)因子（MGF-E）可保護(hù)轉(zhuǎn)染細(xì)胞免受不當(dāng)流體剪切力的傷害[46]。

采用自體MSCs能避免免疫排斥問(wèn)題，當(dāng)自體細(xì)胞供給不足時(shí)會(huì)產(chǎn)生嚴(yán)重的問(wèn)題，這可通過(guò)基因工程技術(shù)增加有絲分裂次數(shù)加以解決。自體移植時(shí)細(xì)胞數(shù)量不足的問(wèn)題主要發(fā)生在老年人，這些患者的MSCs治療潛力和數(shù)量減少。采用基因工程方法能增加移植細(xì)胞的數(shù)量和治療效果。血管內(nèi)注射是創(chuàng)傷較小的一種方法，保護(hù)MSCs免受惡血的影響似乎是關(guān)鍵,但還需要良好的組織靶向性以保證在治療細(xì)

胞在被傳遞到目標(biāo)作用位點(diǎn)前細(xì)胞數(shù)量的損失降到最低，如防止細(xì)胞在肺部及淋巴器官滯留引起的意外損失等。這些細(xì)胞是用來(lái)治療損傷部位，傷處原有的細(xì)胞已嚴(yán)重受損，在這個(gè)充滿破壞性因素的區(qū)域，在此階段對(duì)治療細(xì)胞的保護(hù)似乎也很重要。

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Genetic engineering techniques to enhance therapeutic effects of mesenchymal stem cells

Zhang Jinmei, Yang Yuanrong, Xiong Jianqun, Ding Zhuoling. Department of Pharmacy in Jingzhou Centre Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Jingzhou 434020, China

Mesenchymal stem cells (MSCs) are promising in the field of regenerative medicine due to their relatively easy access and multidifferentiation capabilities, either naturally or induced through cell engineering. Successful MSCs treatment depends on efficient methods of cell delivery and the long-term survival of grafted cells at the target site. The application of genetic engineering technology to modify MSCs before transplantation can accomplish long-term survival. In this review, we describe the genetic engineering strategies to increase the migration ability, decrease senescence and apoptosis and improve the survival of transplantated MSCs.

Mesenchymal stem cells； Genetic engineering； Cell transplantation；Cell movement； Cell survival

2016-07-11）

（本文編輯：陳媛媛）

10.3877/cma.j.issn.2095-1221.2016.05.009

434020 荊州，華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬荊州醫(yī)院藥學(xué)部

楊遠(yuǎn)榮，Email:jzyyyjk@sina.com

張金梅,楊遠(yuǎn)榮,熊建群, 等.應(yīng)用基因工程技術(shù)增強(qiáng)間充質(zhì)干細(xì)胞移植效果[J/CD].中華細(xì)胞與干細(xì)胞雜志:電子版, 2016, 6(5):312-315.