Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (19): 3078-3083.doi: 10.3969/j.issn.2095-4344.2036
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Yu Mingchuan1, Zhao Jinbing1, Yin Ming1, Yin Changchang2
Received:
2019-07-20
Revised:
2019-08-03
Accepted:
2019-09-02
Online:
2020-07-08
Published:
2020-04-09
Contact:
Yin Changchang, MD, Professor, Key Laboratory of Medical Transformation of Jiujiang, Jiujiang University, Jiujiang 332000, Jiangxi Province, China
About author:
Yu Mingchuan, Master candidate, Physician, Department of Orthopedics, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Supported by:
CLC Number:
Yu Mingchuan, Zhao Jinbing, Yin Ming, Yin Changchang. Potentials of pericytes in orthopedics[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(19): 3078-3083.
2.1 周细胞及其他血管周围干细胞的纯化及鉴定 最早是利用细胞表面标志物CD146,也称为黑色素瘤黏附分子(Mel-Cam)来鉴定和纯化周细胞[8-9],为鉴定周细胞迈出重要一步,使得外源性利用周细胞成为可能;然而,CD146的表达也并不是特定于周细胞,CD146也由内皮细胞[10]、血管平滑肌细胞(VSMC)[11]、部分淋巴细胞[12]、肿瘤细胞表达[13]。流式细胞术多色荧光检测(FACS)的出现为周细胞进一步鉴定和纯化带来福音。目前,通过细胞表面标志物(CD146+,CD34-,CD31-,CD45-)来鉴别周细胞成为主流手段[14]。研究人员在脂肪组织中分离出周细胞后,发现脂肪组织的血管内有一种非周细胞,但同样具有间充质干细胞特征的细胞群,这些细胞通过其他的细胞表面标志物(CD146-,CD34+,CD31-)在大动脉和静脉的外膜中被鉴定出来,因此被称为外膜细 胞[15-16]。当CD146+周细胞和CD34+外膜细胞结合使用时,通常称为血管周围干细胞或血管周围间质细胞[14],CD146+周细胞和CD34+外膜细胞之间的细胞差异性与修复功能的相关性目前还尚不清楚。根据上述方法已在多个组织中成功提取周细胞,包括骨骼肌、骨髓、白色脂肪组织、胎盘、胰腺、脐带、心脏、肾脏、髌下脂肪垫和肝脏等[5-6,14,17-19]。值得注意的是,根据同样的细胞标记物,已从其他哺乳动物中成功分离出了周细胞,包括狗[20]、绵羊[21]、马[22],为周细胞介导的组织再生提供了大型动物模型。 2.2 周细胞在骨科中的应用 2.2.1 周细胞促进异位骨形成 人脂肪组织衍生的CD146+周细胞植入严重联合免疫缺陷小鼠肌肉袋时可在其内直接异位骨化[23]。当周细胞以胶原海绵(相对惰性的物质,几乎没有骨诱导性)作为载体植入肌肉袋时,骨化不明显;相反,以骨诱导脱钙骨基质作为载体时,观察到更加稳固的骨化[14]。对同一患者脂肪组织来源的周细胞和外膜细胞进行比较,发现两种血管周围细胞都能诱导产生有血管的异位骨,并且在骨形成程度上没有实质性差异。这项研究初步表明,周细胞和外膜细胞具有相似的成骨潜能,并为以后将这两个细胞群结合在一起研究奠定了基础。将脂肪组织来源的血管周围间质细胞与来自同一患者脂肪基质血管组分分别植入小鼠肌肉袋内进行比较[14],通过显微计算机断层扫描、测量组织形态和免疫组化标志物等方法证实:血管周围间质细胞组的肌肉袋内骨化更为稳固[14],植入部位血管增加更为显著,血管内皮生长因子的表达量更为丰富[24]。总的来说,周细胞和外膜细胞单独或联合使用均能显著促进异位骨形成。 2.2.2 周细胞促进颅骨缺损愈合 在小鼠颅骨缺损模型中[25],首次证实了人脂肪组织来源血管周围间质细胞可诱导颅骨修复。此次实验中,取同一患者脂肪组织中相同细胞量的基质血管组分和血管周围间质细胞分别装载于羟基磷灰石涂层的聚合物支架上,植入顶骨颅骨缺损中,在8周的观察时间内血管周围间质细胞组颅骨缺损处骨痂量明显增加。与肌肉袋内研究相似,血管周围间质细胞治疗后颅骨缺损处血管也明显增加。因此,无论是异位还是骨修复模型中,同源的血管周围间质细胞比基质血管组分具有更强的促成骨和促血管作用。 2.2.3 周细胞促进椎体融合 随着人口老龄化加剧,椎体融合术的需求量在全球范围内逐年递增,在临床中自体骨移植被认为是治疗椎体融合的金标准,然而存在内源性不足等缺陷,研发更为高效易取的骨移植物仍是重点研究方向。在大鼠腰椎融合术模型中,将不同浓度的人脂肪组织来源血管周围间质细胞以脱钙骨基质支架作为载体植入大鼠腰椎中,结果显示大鼠骨痂较对照组增多,骨强度增加,且呈浓度依赖性。与颅骨缺损模型一样,旁分泌介导的骨生成作用在整个椎体融合过程中占主导地位[26]。骨质疏松患者由于成骨细胞数量及骨微环境的限制,自体骨移植疗效有限,可能造成术后恢复期延长,甚至有手术失败的风险。LEE等[27]通过切除小鼠卵巢构建骨质疏松模型,当使用正常剂量血管周围间质细胞时,对于正常小鼠可促进椎体融合,然而对于骨质疏松小鼠疗效较差,当加大血管周围间质细胞剂量时,融合率明显增加。因此,当骨质疏松患者需行脊柱融合,自体骨再生功能不强时,可考虑用血管周围间质细胞代替治疗。 2.2.4 周细胞促进骨折及骨不连愈合 骨折是世界各地骨科病房最常见的疾病之一,愈合过程可能需要6-12周,并且所有骨折中有10%-20%的骨折愈合失败,导致骨不连,并有致残风险。因此加速骨折愈合,缩短病程,减少并发症产生,将会为患者带来更好的疗效。BAJADA等[28]分离提纯小鼠胚胎中的周细胞,进行特异性标记后注入小鼠股骨骨折模型中,这些被标记的周细胞在骨折端新生愈合组织内聚集,可以在体内分化成骨;还有研究表明,在小鼠体内特异性标记周细胞,然后构造股骨骨折模型,3周后在骨折端愈合组织内发现了特异性标记的周细胞,并且表达Runx2和Ⅰ型胶原,证明内源性的周细胞也能分化为成骨细胞,进而促进骨折愈合。 萎缩性骨不连与骨折愈合的生物学效应失效有关,其主要原因是萎缩性骨不连断端血供及成骨活性差,其内的间充质祖细胞含量、增殖能力及成骨能力均降低[29]。在大鼠胫骨萎缩性骨不连形成3周后,经皮将CD146+脂肪组织来源周细胞注射于骨不连断端,骨折端骨痂量明显增加并促进其骨化,最终促进骨不连断端愈合[30]。 2.2.5 周细胞在关节软骨中的作用 尽管周细胞和其他血管周围干细胞显示出强大的骨形成潜力,但目前对促进软骨生长则知之甚少。在发育中胎儿的骨骺软骨的血管周围发现了周细胞[31]。半月板软骨的发育也与周细胞有关,OSAWA等[32]从胎儿半月板分离出周细胞,他指出半月板有血管部分的周细胞比相对无血管部分含量更高,并证明周细胞可能参与半月板软骨的发育。在骨性关节炎中,周细胞功能作用还不清楚。SU等[31]证明了CD146+软骨生成细胞群比脂肪来源间充质干细胞具有更高的软骨生成潜能。研究表明,刺激Wnt/β-catenin信号通路可以增强周细胞的软骨分化[33]。LI等[34]通过组合生长因子来加强体外周细胞软骨形成潜力。与其他生长和分化因子组合相比,尼尔样1型生长因子、转化生长因子β3、重组人骨形态发生蛋白6的组合可显著加速血管周围间质细胞软骨分化,这种生长和分化因子组合并没有促进软骨细胞肥大、纤维化或成骨分化标志物的上调,表明这种方法具有潜在临床实用性。 2.2.6 在骨科运动医学中的周细胞 跟腱病是一种在骨科、运动医学及康复医学等医学学科中常见的肌腱病,以跟腱退行性病变为主。在大鼠跟腱横断模型中,DEVANA等[35]将人脂肪来源的周细胞制成水凝胶,植入大鼠断裂跟腱模型中,3 d后检测到注射的周细胞定位于横断面的周围,3周后取出大鼠跟腱行生物力学分析,发现跟腱抗牵拉能力明显强于空白对照组。 前交叉韧带断裂是膝关节损伤中的常见疾病,目前自体和同种异体肌腱移植重建韧带仍是治疗的重要方式,但只有达到牢固的腱骨愈合才能提供有效的力学强度,然而腱骨的特殊结构往往导致其愈合能力较差,术后愈合时间长,而愈合时间的长短直接影响到患者早期的康复训练,可见促进腱骨愈合是手术成败的关键问题。CUTI等[36]培养股薄肌腱组织、股薄肌肉组织、半腱肌腱组织和半腱肌肉组织中肌源干细胞和肌腱源性干细胞,分离鉴定其中周细胞,发现肌肉组织中的周细胞明显多于肌腱组织。现在大部分前交叉韧带重建手术中行自体肌腱移植时,往往剔除肌腱周围肌肉组织,CUTI等[36]认为保存部分肌肉组织,有可能更好地促进腱骨融合,当行韧带重建时,移植一定量的血管周围间质细胞可能促进腱骨融合。 2.2.7 周细胞在骨科中其他方面的应用 (1)周细胞防止长时间固定后的骨骼肌萎缩:当外伤致骨折、肌腱及韧带受损时,往往需行一段时间的制动治疗,这段时间可以是全身固定(卧床休息),也可以是四肢固定。这一段时间的制动治疗对骨折愈合或肌腱修复等病情恢复至关重要,长时间的制动可能导致骨骼肌质量和功能显著降低,特别是对于老年人,严重者可致残。然而临床上尚无预防肌肉萎缩或促进其恢复的有效治疗方法,MICHAEL等[37]将小鼠后腿屈曲固定2周,与对照组相比,固定组小鼠胫骨前肌明显萎缩,肌纤维横截面积变小,与正常对照组相比,胫骨前肌中NG2+Lin2-周细胞含量明显减少。然而,将小鼠固定解除,使其活动2周左右以后,小鼠后肢功能基本恢复,周细胞含量同正常无异。将外源性周细胞植入萎缩胫骨前肌中,肌纤维横截面积逐渐恢复,并且促进肌内毛细血管增生,减少组织缺血及缺氧。移植周细胞可以防治因长期制动而引起的肌肉萎缩,为骨科康复治疗带来新方向。 (2)周细胞促进伤口愈合及减少瘢痕形成:如何促进慢性伤口愈合和防止急性创伤性伤口结疤,无论在骨科还是其他领域一直是难以克服的难题。BODNAR等[38]用8 mm环形打孔器在小鼠背部打出一全层伤口,行抗炎、抗感染及止痛治疗后,在小鼠伤口内移植周细胞,从第3天开始到观察结束,周细胞组较成纤维细胞组和空白对照组伤口愈合更快,有着更为良好的愈合趋势,并且瘢痕形成更少。周细胞治疗后伤口内的浆细胞、中性粒细胞及淋巴细胞等炎性细胞含量更少,并且白细胞介素10和肿瘤坏死因子α等炎性细胞因子含量也同样降低,肉芽组织和新生血管则形成得更多。瘢痕形成和增生性瘢痕形成的标志是Ⅰ型胶原束形成和沉积。在无瘢痕伤口愈合过程中,观察到Ⅲ型胶原比Ⅰ型胶原更 多[39-40]。从周细胞组、成纤维细胞组和空白对照组伤口检测Ⅰ型和Ⅲ型胶原蛋白mRNA水平显示出显著差异,周细胞组伤口组织中Ⅲ型胶原蛋白mRNA表达更多,Ⅰ型胶原蛋白含量更少,与瘢痕减少结果一致,周细胞治疗组瘢痕明显少于成纤维细胞组和空白对照组。周细胞在促进慢性伤口愈合、防止瘢痕形成方面,同样具有明显优势。 2.3 周细胞治疗骨科疾病的作用机制研究 如上文所述,在体内移植的血管周围间质细胞可直接分化为成骨细胞。但是,物种特异性抗原免疫组化检测显示,新生骨中的成骨细胞和骨细胞更常见于其宿主,而不是供体来源。例如,将人类血管周围间质细胞植入大鼠模型中,大鼠源性成骨细胞的数量比人源性成骨细胞的数量多出3.8-10倍甚至更多[41]。因此,大部分新生骨并不是血管周围间质细胞直接分化形成的,而是由宿主自身产生,周细胞可能存在一个潜在的旁分泌机制发挥其主要的骨愈合作用。支持这一假设证据显示,周细胞具有强大的分泌细胞因子能力,与基质血管组分或脐血间充质干细胞相比,人周细胞分泌的肝素结合表皮生长因子、成纤维细胞生长因子2、血管内皮生长因子和角蛋白生长因子多5-20倍。RNA测序进一步证实这一假设,周细胞表达骨形态发生蛋白转录物(包括骨形态发生蛋白2,4,7)明显升高,以及成纤维细胞生长因子和血小板生长因子转录物也呈现高表达。由此可见,周细胞的旁分泌系统功能十分强大,在促进骨折愈合过程中占主导地位[42]。周细胞的治疗效果存在明显共性[43-46],即调节微血管稳定性、血管生成和毛细血管血流动力学等,然而此种效果很可能来源于其旁分泌体系[47]。旁分泌体系最重要的途径是通过自身分泌外泌体实现的[48],外泌体是一种直径为40-100 nm微小囊泡,具有脂质双层膜结构,可携带脂质、核酸和蛋白等多种活性物质,是介导细胞间交流的重要介质[49]。周细胞来源外泌体已被证实可治疗脊髓损伤,在急慢性缺血缺氧性疾病或血管病变性疾病中,周细胞来源外泌体均有可能有着良好的疗 效[50-51]。 2.4 周细胞及其他血管周围干细胞相对其他移植物的优势 自体骨移植最常见的为髂骨植骨,已广泛应用于临床,并取得良好的疗效,但是往往需另行切口,延长了手术时间,增加了手术费用,并且髂骨松质骨有限,在需大量自体骨时无法有效供应。骨髓间充质干细胞虽然获取简单,在体外能大量增殖,然而骨髓间充质干细胞分离培养中未经特异性纯化,即使在培养过程中逐渐占主导地位并成为最丰富的细胞类型,但仍存在残余的异质性,并且通过体外培养和传代是非常耗时的,在紧急情况下无法大量获取,长时间的细胞培养更会增加感染、免疫原性、遗传不稳定性、肿瘤原性等风险[52-54]。异体骨、骨形态发生蛋白或其他植入材料存在免疫排除等风险,并且价格高昂,增加了患者负担。周细胞则是利用荧光激活细胞分类而不是基于体外培养获取细胞。据报道,每100 mL脂肪组织提取物中可纯化出1 500万株血管周围间质细胞[55]。从临床角度来看,大量自体细胞的存在意味着避免了内源性供应不足等问题,无需体外培养细胞显著降低了住院时间、成本和风险,并赋予细胞群体更大程度的同质性。 "
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