Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (7): 1102-1106.doi: 10.12307/2022.151
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Wu Weiyue, Guo Xiaodong, Bao Chongyun
Received:
2020-11-02
Revised:
2020-11-05
Accepted:
2020-12-07
Online:
2022-03-08
Published:
2021-10-29
Contact:
Bao Chongyun, MD, Professor, State Key Laboratory of Oral Diseases, Sichuan University, Department of Alveolar and Maxillofacial Implant Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
About author:
Wu Weiyue, Master candidate, State Key Laboratory of Oral Diseases, Sichuan University, Department of Alveolar and Maxillofacial Implant Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
Supported by:
CLC Number:
Wu Weiyue, Guo Xiaodong, Bao Chongyun. Application of engineered exosomes in bone repair and regeneration[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(7): 1102-1106.
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2.1 骨缺损修复的研究现状 肿瘤、创伤、感染及先天畸形导致的各种骨缺损在临床上十分常见,小范围骨缺损或创伤通常可自我修复;节段性或较大而复杂的骨缺损,不能实现自我形态修复及功能重建,因此需要利用特殊的治疗手段(如牵张成骨)及骨替代物(如自体骨、人工骨替代材料)完成。牵张成骨技术对长骨的缺损修复或部分骨增量的治疗效果较好,但对形态复杂的骨缺损,该技术应用有限,而且治疗周期长、流程繁琐也限制了其临床应用[1]。骨替代物中,自体骨移植来源于受者本身,骨移植后与受植区相容性较好,一直被认为是骨缺损修复的“金标准”,目前在临床应用中仍占主要地位[2]。然而自体骨移植由于需在身体其他部位取骨,常需开辟第二术区,术后会在取骨区域遗留瘢痕,还可能继发取骨区域的感染及功能障碍;另外,自体骨取骨量有限且受供区骨形态影响,常不能准确地恢复缺损区域的形态与功能[3]。异体及异种骨移植虽然可以避免开辟第二术区的问题,但存在潜在的免疫排斥反应及传播疾病的风险,未被广泛应用[4]。骨替代材料如磷酸三钙陶瓷等,因缺乏良好的骨诱导性和力学性能,目前仍无法满足临床需求,而且其骨整合和体内代谢等问题仍处于优化表面结构、材料性质和表面性能的实验阶段[5-7],需要进一步探究。以细胞为基础的骨组织工程具有优秀的促成骨能力[8-9],但其缺点(细胞无限繁殖癌变、免疫抵抗等)也十分明显。外泌体作为细胞的衍生物,不会产生免疫抵抗,同时负载了细胞活性物质,这使其成为目前骨缺损修复研究的热点。 2.2 外泌体与骨修复再生 2.2.1 外泌体的定义及功能 外泌体是天然存在的直径介于30-150 nm的细胞外囊泡,几乎所有细胞都可分泌[10-12],其中包含多种蛋白质、脂质和核酸(mRNA、miRNA等)等生物活性物质[13-14],具有介导细胞间通讯、促进抗原提呈等功能[15]。外泌体膜具有脂质双分子层结构,由丰富的胆固醇、鞘磷脂、磷脂酰丝氨酸组成,与其亲代细胞的细胞膜脂质组成高度相似[16],为选取治疗使用的供体细胞提供依据。现阶段研究发现Rab蛋白、膜联蛋白、整联蛋白、四跨膜蛋白、MHCⅡ类、细胞黏附分子与外泌体运输蛋白质、mRNA/miRNA功能有关[17-20]。除此之外,相对于细胞移植、人工合成材料,外泌体还具有相对无毒性、高稳定性、可进入血脑屏障和具有靶向识别能力等优点[21-25],这些特点使外泌体成为目前组织再生领域的明星物质,在疾病治疗、组织再生领域展现出优秀的潜力[26]。 2.2.2 外泌体在骨修复再生中的应用 由于外泌体的天然优势,近年来许多研究开始探究其促进骨缺损修复再生的可能。QI等[27]将人诱导多功能干细胞诱导分化形成间充质干细胞并提取其分泌的外泌体,然后对患有骨质疏松症的颅骨缺损小鼠模型进行体内实验,结果表明:人诱导多功能干细胞衍生的间充质干细胞来源外泌体(hiPSC-MSC-Exos)可以刺激骨形成,进一步研究表明hiPSC-MSC-Exos通过激活PI3K/Akt信号通路,上调Runx2、Ⅰ型胶原和碱性磷酸酶的表达,从而促进成骨细胞的骨向分化。ZHANG等[28]在研究大鼠颅骨缺损修复时,使用了人骨髓间充质干细胞来源外泌体与β-磷酸三钙组成的复合支架(实验组)和纯β-磷酸三钙支架(对照组),结果发现实验组的外泌体可以通过激活PI3K/Akt途径,诱导人骨髓间充质干细胞的增殖、迁移和分化,促进骨再生。除此之外,天然外泌体还可以通过促进血管内皮细胞增殖、迁移及管样分化[29-30],为新骨提供养分从而促进骨再生。 2.3 工程化外泌体的优势及一般制备方法 2.3.1 工程化外泌体的优势 随着研究的深入,天然外泌体作为药物递送系统修复骨缺损的缺陷也逐渐暴露。①天然外泌体靶向性差:成熟外泌体被供体细胞排出进入体液循环,循环过程中部分外泌体被体内其他细胞摄入而无法全部精准达到需要治疗的区域;②有效的天然外泌体数量过少:细胞产生的外泌体全部进入体液循环导致细胞摄入的外泌体不全都具有治疗作用;③负载分子含量无法达到治疗浓度:外泌体在供体细胞中加工组装,继承了供体细胞的生物活性物质,导致外泌体负载的治疗所需物质含量占比低。因此,研究者开始人工制备特殊的外泌体——工程化外泌体来达到治疗目的[31]。工程化外泌体是为达成目的人工改性制备的外泌体,相比于天然外泌体,它可以在外泌体膜上添加特定的配体从而提高其靶向性,也可以改变供体细胞的培养环境提高某种基因的表达从而得到所需的高表达外泌体,也可以直接改变供体细胞的DNA、RNA得到富含目的成分的外泌体。 2.3.2 工程化外泌体的一般制备方法 目前,可通过电穿孔、化学共轭法、孵育法等方法制备得到含有选定siRNA、miRNA、药物和酶等物质的工程化外泌体[32]。除此之外,也可以通过改变供体细胞生长环境、遗传物质等方式,得到特殊的工程化外泌体。常见的工程化外泌体制备方法和各自的优缺点见表1[33-42]。 "
使用上述方法,工程化外泌体不仅可以装载亲水/不亲水小分子,还可以运输蛋白质、RNA、DNA等大分子物质,还可以通过脂质膜上的共价键、配体特异性结合抗体等,见图2[43]。 2.4 工程化外泌体在骨修复再生中的应用 研究发现改变供体细胞培养环境得到的工程化外泌体可以显著促进骨再生。LI等[44]发现缺氧环境下培养的骨髓间充质干细胞来源外泌体可以促进成骨,体外实验发现该外泌体可以增强血清骨钙素和碱性磷酸酶的基因表达,从而促进骨髓间充质干细胞的成骨分化;该外泌体还可以促进人脐静脉内皮细胞的增殖、迁移和管状结构的形成;对类固醇诱导的股骨头缺血性坏死模型进行体内实验,工程化外泌体组检测到了更高的血管密度和更密集的骨小梁组织生成。SAKAGUCHI等[45]也发现低氧环境刺激骨髓间充质干细胞产生特殊的外泌体,与正常环境培养得到的骨髓间充质干细胞来源外泌体相比,不仅能增强ALP、Runx2、COL1和COL2的基因表达,还能增强人脐带内皮细胞的管结构形成,体内实验结果也显示工程化外泌体组的新骨形成率高于天然外泌体组。 使用孵育法也可得到促成骨的工程化外泌体。LIANG 等[46]使用低剂量的二甲基草酰甘氨酸处理骨髓间充质干细胞来源外泌体用于大鼠临界颅骨缺损修复,实验发现该工程化外泌体通过激活AKT/mTOR途径,促进人脐静脉内皮细胞生成血管和骨再生。 使用化学共轭法可以使具有促成骨作用的外泌体靶向到指定细胞。LUO等[47]为解决骨髓基质细胞来源外泌体不能与骨髓间充质干细胞靶向结合的问题,使用化学共轭法制备了可与骨髓间充质干细胞特异性结合的工程化外泌体;对切除卵巢的骨质疏松小鼠模型进行体内实验,结果显示工程化外泌体组骨量恢复明显高于天然外泌体组,且骨折愈合速度也有所加快,此实验证实了该工程化外泌体具有靶向骨髓间充质干细胞并促进骨再生的作用。 使用转染法可得到精确表达促进成骨基因的工程化外泌体。罗月等[48]利用miR-764慢病毒载体转染大鼠骨髓间充质干细胞,得到过表达促成骨miR-764的外泌体;体内实验结果显示,脱钙骨基质与工程化外泌体组成的混合支架植入大鼠颅骨缺损部位后,显著促进骨缺损部位的细胞浸润、胶原沉积、骨钙素和骨桥蛋白表达量增加以及微血管结构生成。另一项研究显示Akt修饰的人脐带间充质干细胞来源外泌体显著促进血管内皮细胞的增殖和迁移、管状结构的形成和体内血管的形成[49]。"
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