Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (32): 5220-5224.doi: 10.3969/j.issn.2095-4344.2014.32.023
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Gao Qing1, Li Shu-ren2
Received:
2014-07-10
Online:
2014-08-06
Published:
2014-09-18
Contact:
Li Shu-ren, M.D., Professor, Chief physician, Master’s supervisor, Department of Cardiology, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
About author:
Gao Qing, Studying for master’s degree, Hebei General Hospital Affiliated to Hebei Medical University,, Shijiazhuang 050051, Hebei Province, China
CLC Number:
Gao Qing, Li Shu-ren. The preclinical and clinical application of genetically modified stem cells for the treatment of myocardial infarction[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(32): 5220-5224.
2.1 常用于移植的干细胞类型 干细胞属未分化的细胞,具有自我更新能力和多向分化潜能。可通过一种或多种联合机制参与心脏修复的过程,包括分化为成熟心肌细胞、与宿主心肌细胞建立电-机械偶联或通过旁分泌活动产生生物活性分子等,而后者则被认为是改善左室功能的主要机制[1]。目前用于移植的干细胞除了传统的的胚胎干细胞及成体干细胞以外,诱导多能干细胞的出现又为细胞移植类型提供了新的选择。 2.1.1 骨髓间充质干细胞 骨髓间充质干细胞因其具有体外扩增能力强、免疫原性低、分泌生物活性物质多等优点而被广泛应用于基础及临床研究。2012年国际循证医学协作组完成关于骨髓细胞治疗急性心肌梗死的荟萃分析[2],结果发现:干细胞可提高左室射血分数,减少梗死面积并改善左室重构且获益可长期持续。该结果肯定了骨髓细胞在心肌修复中的作用,然而临床移植的效果可能受很多因素的影响,比如患者年龄偏大、骨髓中成体干细胞含量较低,缺氧条件下细胞存活受限,细胞迁移及定植率较低等。此外,应用骨髓间充质干细胞的安全性问题尚值得考虑。因此,采用各种预处理方法诱导其向心肌细胞定向分化将尤为必要。 2.1.2 骨骼肌干细胞 与骨髓间充质干细胞一样,骨骼肌干细胞具有很多优点,包括安全性高、易于获取、不涉及伦理及宗教问题、易于在体外扩增并向肌源性分化且不用担心致瘤性的问题。此外其抗缺血特性及低免疫原性,为其在临床试验中的广泛开展提供可能,然而,其分化的心肌细胞却不能与宿主细胞间通过缝隙连接形成电-机械偶联,最终导致心律失常的发生。另外SEISMIC研究[3]发现,骨骼肌干细胞移植4周后,心脏收缩功能并未明显提高。因此,骨骼肌干细胞的临床应用前景还有待考证。 2.1.3 心肌干细胞 人们已经从多种动物及人体内分离出心肌干细胞,并且发现在人类心脏组织中存在血管源性(ckit+/KDR+)及肌源性(ckit+)两类心肌干细胞[4]。多项动物研究发现移植后的心肌干细胞不仅能向肌源性血管分化,还可释放多种有益的旁分泌因子,如诱导内皮细胞迁移及保护心肌细胞的可溶性vCAM-1 [5]。鉴于动物实验获得的可喜成果,心肌干细胞Ⅰ期临床试验也在陆续开展,其中较为引人关注的有SCIPIO研究[6]和CADUCEUS研究[7],二者均证实心肌干细胞移植治疗心肌梗死是安全可行的。并且SCIPIO研究的最终结果显示:急性心肌梗死患者在接受经冠状动脉移植心肌干细胞后,心肌梗死面积减少、心功能得以改善,2年随访结束时,患者也未出现严重不良反应。然而该结果还有待进一步大规模、多中心的Ⅱ期及Ⅲ期临床试验的验证。 2.1.4 胚胎干细胞 胚胎干细胞是从哺乳动物的囊胚内细胞群中分化出来的一种原始、高度未分化细胞,具有无限的自我更新能力。研究发现,由人胚胎干细胞分化来的心肌细胞在功能上与人类心肌细胞极为相似[8],移植胚胎干细胞及其分化的心肌细胞均可使梗死的心肌再生并使左室收缩功能改善[9]。另外胚胎干细胞还展现出较成体干细胞更为显著的旁分泌作用[10]。这些旁分泌因子除了可减少宿主心肌细胞的凋亡,还可通过激活内源性ckt+Flk1+的内皮祖细胞来提高心脏的血管再生能力[11]。然而不幸的是胚胎干细胞移植入心脏后表现出潜在的致瘤性[12]。此外,应用过程中涉及到的道德、伦理以及免疫问题也是限制其在临床广泛开展的重要因素。 2.1.5 诱导多能干细胞 自Takahashi等[13]首次报道了通过反转录转染的方式将干细胞相关基因导入小鼠体细胞,进而得到分化全能性的诱导多能干细胞后,无疑给干细胞领域注入了一股新鲜的血液。诱导多能干细胞在形态、培养条件及分化特点等方面与胚胎干细胞极为相似,且因具有取材方便,无免疫排斥反应及不存在道德及伦理问题而颇受关注。有研究证明,由诱导多能干细胞分化的心肌细胞可表现出自发收缩活动并表达心肌特异性蛋白标记物及转录因子[14-15]。然而,它和胚胎干细胞一样也表现出一定的致瘤性[16]。因此,优化移植细胞、实施基因重编,采用心肌细胞来源的诱导多能干细胞等尝试极为必要。在急性心肌梗死动物模型中,移植成纤维源性的诱导多能干细胞后心肌表现出极大地再生能力[17]。同样心肌源性诱导多能干细胞不仅大量的存活,而且在移植2-4周后也未发现肿瘤形成。最近有研究证实采用反转录病毒转导的方法将4种转录因子对骨骼肌干细胞进行重排后可产生诱导多能干细胞[18],这些诱导多能干细胞在理想的培养条件下可分化为心肌细胞。有研究者将诱导多能干细胞、衍生的心肌细胞以及骨骼肌干细胞分别移植到急性心肌梗死的心脏内,结果发现,移植有诱导多能干细胞衍生的心肌细胞的小鼠心功能改善最为明显,且未发现有肿瘤形成[16]。 2.2 治疗性基因的选择 通过特定基因修饰细胞的方法可弥补单纯干细胞移植疗效的不足。目前基因转染干细胞移植治疗缺血性心脏病研究的目的基因大致分抗凋亡、促血管新生、促归巢及抗炎四大类。 2.2.1 延长寿命及增强抗凋亡能力的基因 移植的干细胞在梗死心肌恶劣的微环境下较低的生存力是干细胞治疗用于临床的一大障碍[19]。为此,人们尝试用抗凋亡作用基因如Pim-1、Akt及 Bcl-2等来对干细胞进行移植前修饰。研究表明,将Pim-1修饰的细胞移植到体内后细胞存活量显著增加且心功能明显改善[20]。移植糖原合成酶激酶-3b(GSK-3b)修饰的骨髓间充质干细胞不仅能提高移植细胞生存力还可促使其向心肌表型分化[21]。另外,采用组织性激肽释放酶基因修饰后的间充质干细胞可抵御缺氧诱导的凋亡及凋亡控制因子caspase-3的激活,并增加抗凋亡基因Akt的磷酸化[22]。可见经抗凋亡基因修饰后的干细胞更能充分发挥其治疗作用。 2.2.2 促进血管生成的基因 与血管生成有关的基因包括血管内皮生长因子、血管生成素1、胰岛素样生长因子、肝细胞生长因子及碱性成纤维细胞生长因子等。其中血管内皮生长因子除了能促进血管生成,还能激活心肌内源性修复机制,减少梗死部位的炎症反应[23];血管生成素1不仅能促进血管生成还可以提高其移植细胞生存率。肝细胞生长因子是多种组织及细胞的生长因子,除促血管生成外,还可提高骨髓间充质干细胞的存活、改善组织重构。同样胰岛素样生长因子除了能促进毛细血管生长还有促进骨髓间充质干细胞向梗死部位迁移的作用。Shh基因可调控血管径加粗、变长和分叉,并可促进众多血管生成因子的分泌,Durrani等[24]已在动物实验中验证了其血管再生作用,另外Shh基因还具有减少心肌细胞凋亡,促进骨髓来源内皮祖细胞迁移等作用。相信Shh基因会引起更多研究者的重视。 2.2.3 促进靶向归巢的基因 无论采用何种移植方式,干细胞能否有效地归巢,将直接影响最终疗效。心肌梗死发生后,受损心肌组织将释放大量的细胞因子诱导干细胞向心脏归巢,如SDF-1、MCP-3、GDF-15、bFGF、GRO-1等[25]。然而这些因子的释放时间极为短暂,其中最受关注的SDF-1释放仅能持续1周,而MCP-3则不足10 d[26]。因此人们设想是否可在移植前对干细胞进行促归巢相关基因修饰进而提高其移植效率。不久,Pasha等[27]证实,采用SDF-1修饰的骨髓间充质干细胞,不仅能促进干细胞迁移,还可改善细胞存活、促进血管生成。此外,将趋化因子SDF-1的受体CXCR4修饰的骨髓间充质干细胞静脉移植至缺血再灌注大鼠模型中,发现归巢的细胞数目明显增加、心功能得以改善,心室重构程度也减低[28]。 2.2.4 抗炎基因 免疫炎症反应是心肌受损后,机体自发启动的保护性修复机制。然而过度激活的炎症反应将导致心肌的进一步损伤。炎症反应发生时常伴有大量炎性因子的释放,如肿瘤坏死因子α、C-反应蛋白、白细胞介素1β及白细胞介素6等,其中尤以肿瘤坏死因子α最为引人关注。传统的抗炎药物治疗均未取得理想的疗效,而将肿瘤坏死因子的受体(TNFR)基因修饰的间充质干细胞移植到缺血的心肌组织中,心肌细胞凋亡却明显减少,心功能也较前改善[29]。 近来研究发现,普遍存在于人和哺乳动物细胞内缺氧诱导因子1α可在缺氧条件下稳定表达。缺氧诱导因子1是具有转录活性的核蛋白,具有广泛的靶基因谱,能够控制下游100多种基因的表达[30],包括VEGF、EPO、GLUT-1、e-MET等,这些基因表达后参与红细胞及血管生成,参与核苷、氨基酸、糖的代谢和细胞存活、凋亡等活动,维持组织、细胞在缺氧条件下内环境的稳定[31]。 2.3 基因修饰的载体选择及移植途径的探索 2.3.1 基因修饰载体的选择 基因治疗中载体的选择是影响目的基因能否发挥治疗作用的关键。常用的表达载体包括病毒载体和非病毒载体,其中病毒载体的应用更为广泛。 病毒载体:随着对病毒生物学性质的深入了解,病毒因高效的转染率而成为基因转导中的常用载体。目前病毒载体的种类较为丰富,包括反转录病毒、慢病毒、腺病毒、腺相关病毒等,其中反转录及慢病毒载体可将目的基因整合到靶细胞的基因组中而长期表达,但整合作用会影响内源基因和转基因的表达,而且应用慢病毒时有潜在感染HIV-1的危险。腺病毒因免疫原性、致癌性及携带基因能力有限、目的基因表达时间相对短暂等缺点而不宜在临床应用。然而腺相关病毒不与靶细胞染色体整合,并且能够在短时间内高效的表达目的基因。因此,腺相关病毒被视为最有前途的基因转移载体之一。 非病毒载体:尽管与病毒载体相比非病毒载体转导效率较低,但因其不具有免疫原性、致癌性等缺点,对人体而言则相对安全。在非病毒转染方法中,电穿孔、微量电穿孔及核转染是目前最有效的转染方法。除了大量基于脂质体及微囊泡的基因传递系统,纳米微粒在基因转染中的作用也越来越受关注[32]。另一重要进展是利用转座子为中介将DNA传递至细胞,与病毒载体相比转座子载体功能更多、安全性更高、可控性更高。其中,piggyBac转座子已成为干细胞转染中最为活跃的载体[33]。近期,piggyBac转座子已被用于构建小鼠及人类的诱导多能干细胞[34],转座子已成为哺乳动物细胞转染较为适宜的载体。 2.3.2 基因途径的选择 有效的干细胞移植途经应该是将足够数量的细胞移植至心脏靶区,并保证细胞较高的定植率及存活率。因此移植途径的选择是决定临床疗效的重要因素。常用干细胞移植途径包括经静脉、经冠状动脉、经心外膜、经心内膜和经冠状窦注射等[35-36]。静脉移植虽易于操作、创伤小,但细胞常因不能有效的归巢而影响移植效率。经开胸行心外膜或心内膜心肌内注射的方法创伤虽大,却能保证损伤的心肌局部足量的细胞。临床上最常用的方法是经导管冠脉内注射,该方法可最大程度的使细胞定植于损伤心肌,但却存在微血栓形成及细胞滞留率低的问题。与冠脉内注射一样,经冠状窦途径注射也可保证移植细胞准确定植于靶区,该方法正被应用于临床试验中[37]。近几年,新兴技术组织工程贴片法正在试用中[38],但因存在众多不确定因素而尚未应用于临床。 2.4 基因治疗联合干细胞移植在心血管疾病中应用 除了在心肌梗死及缺血性心脏病中的广泛应用,基因修饰干细胞移植治疗还在高血压、心律失常、扩张性心肌病及心功能不全等疾病领域展现出极大的发展空间。内皮一氧化氮合酶(eNOS)基因是一种能够抑制损伤血管增生并使血管发生再内皮化进而预防血管再狭窄的基因,有研究证实,将内皮一氧化氮合酶基因导入动物后,发现它能降低血压、减少交感神经系统的活性、改善胰岛素抵抗,进而防止肾性高血压的进展[39]。GATA-4是一种调控抗凋亡因子适应性以及与心脏肥大有关的基因,因此GATA-4可以逆转梗死左室的重构,为心脏衰竭的治疗提供新的方向[40]。相信随着基因治疗联合干细胞移植技术的蓬勃开展,必将使更多临床疾病的治疗获益。"
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