Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (1): 154-158.doi: 10.3969/j.issn.2095-4344.2003
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Liu Tingting1, 2, Han Changxu2, Wang Guoqiang2
Received:
2019-04-24
Revised:
2019-04-30
Accepted:
2019-06-12
Online:
2020-01-08
Published:
2019-12-13
Contact:
Wang Guoqiang, Chief physician, Master’s supervisor, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, Inner Mongolia Autonomous Region, China
Han Changxu, MD, Associate chief physician, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, Inner Mongolia Autonomous Region, China
About author:
Liu Tingting, Master candidate, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China; the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, Inner Mongolia Autonomous Region, China
Supported by:
CLC Number:
Liu Tingting, Han Changxu, Wang Guoqiang. New insight into cell transplantation for repairing intervertebral discs[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(1): 154-158.
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2.1 固有再生 椎间盘退行性变的特征表现为失活细胞数的增加和细胞衰老速度加快。椎间盘祖细胞也随着年龄的增长而减少。大多数组织受到损伤时,都具有让周边新的、活跃的细胞向损伤组织趋化和迁移的能力,从而使受损组织得以再生。有研究对原位细胞募集到椎间盘的潜力进行了探索。HENRIKSSON等[9]通过对兔的研究揭示了干细胞迁移进入邻近软骨膜和外韧带区的纤维环外层的途径。ILLIEN-JUNGER等[10]把牛的整个椎间盘在体外培养,发现外源性的间充质干细胞能够通过终板浸润椎间盘,且退化状态椎间盘的浸润速度更快。这两项研究都表明椎间盘内细胞募集是可能的,但是这种可能仅在终板和大部分纤维环等有血管的组织中实现。椎间盘是非血管性质,细胞向髓核和内部纤维环的迁移很有限。另一个固有再生源是一种特有的祖细胞群。在对完整的椎间盘提取物的研究中,鉴定出间充质干细胞是CD70+CD90+CD105+CD34-CD14-CD79- CD45-CD11b-CD19-HLADR-塑料黏附细胞群,它们具有体外自我更新和多谱系分化的潜能,但是体内特征和定位仍未确定。SAKAI等[11]研究确定了鼠和人的髓核特异性Tie2+和GD2+祖细胞群。该种群有较强地产生和增殖细胞外基质的能力,在体内和体外均表现出多能分化能力。该细胞群的基因靶点可能在研究刺激和诱导组织修复方面有好的前景。在体外实验中,ANG-1能刺激Tie2+细胞,促进细胞集落形成[12],降低凋亡率。因此,选择合适的细胞类型和细胞来源对椎间盘的成功再生至关重要[13]。 2.2 细胞来源 椎间盘的髓核细胞处于高渗、酸性、低糖和低氧的环境中而缺乏血液供应,特殊的生存环境决定了髓核细胞与其他细胞的特性明显不同,髓核细胞持续表达缺氧诱导因子1α,在不同氧气体积分数的条件下缺氧诱导因子1α都能诱导髓核细胞适应糖酵解,使髓核细胞能够很好地利用有限的营养物质进行生存[14],同时缺氧诱导因子1α促进了髓核特异性细胞外基质的产 生[15]。由于髓核细胞与软骨细胞的免疫表型及分子标记相同,能向类软骨细胞分化的细胞就被认为是椎间盘再生可能的候选细胞。干细胞成为近年来许多研究者用来促进椎间盘再生的首选细胞,一篇近期的Meta分析表明,将干细胞移植到动物模型的椎间盘内可显著延缓椎间盘退变发生的速度[16]。 目前作为椎间盘的再生细胞来源大体类型可分为5类:①胚胎干细胞[17],是从早期胚胎(原肠胚期之前)或原始性腺中分离出来的一类细胞,1981年EVANS和KAUFMAN首次成功在小鼠体内获得,在体外培养时可以无限增殖、自我更新和多向分化。它与早期胚胎细胞的形态结构相似,结构简单,细胞核大,且有1个或几个核仁,胞核中多为常染色质,胞质胞浆少。该细胞具有很大的应用潜力,然而它固有的肿瘤发生风险和伦理问题也需要谨慎对待;②诱导多能干细胞[18],率先被日本京都大学YAMANAKA研究小组于2006年制备成功,2007年该小组将人类的成纤维细胞诱导为诱导多能干细胞,该细胞与胚胎干细胞有相似的分化能力,目前已成功地被分化为多种特异性细胞,它的出现对于组织工程及干细胞研究具有划时代的意义。最近的研究表明,诱导多能干细胞可以诱导为软骨细胞样细胞[19],与胚胎干细胞一样其应用潜力很大,但是肿瘤发生风险和伦理问题也必须重视;③间充质干细胞,是干细胞家族的重要成员,来源于发育早期的中胚层和外胚层,最初在骨髓中得到,因其具有自我复制能力和多向分化潜能等特点而日益受到人们的关注。间充质干细胞在体内或体外特定的诱导条件下,可分化为多种组织细胞,连续传代培养和冷冻保存后仍具有多向分化潜能。间充质干细胞是多能细胞,易于从各种组织(例如脐带、骨髓和脂肪组织)获得,且其分化为何种细胞取决于移植的部位,可作为理想的种子细胞用于衰老和病变引起的组织器官损伤修复[20];当然,不同来源的间充质干细胞倾向分化途径不同[21];④软骨细胞样细胞和椎间盘衍生细胞[22]。软骨细胞样细胞和椎间盘衍生细胞天生具有产生髓核样细胞外基质的能力,并能在缺氧条件下存活。然而,它们的细胞数量太少,可用的组织来源也通常受损或患病。为此,MOCHIDA等[23]通过对间充质干细胞共培养系统来重新激活从退变椎间盘提取的髓核细胞。结果显示:与未共培养的细胞相比,再活化的细胞增殖力显著增强;没有共培养的髓核细胞在培养7 d后细胞数没有增加。此种方式下髓核细胞的重新激活为规避细胞退化和退化的椎间盘组织提供了一个有前途的选择。MEISEL等[24]研究未对椎间盘衍生的软骨细胞实施再激活方法,且他们的样本仅限于椎间盘突出患者,因此衰老问题不是该项研究的影响因素。但是,被切除的突出的椎间盘组织可能成为椎间盘衍生细胞的来源。以上两种研究中均观察到了疼痛和MRI影像评估的改善。因此,椎间盘衍生的细胞或软骨样细胞有改善椎间盘的能力。目前临床前研究表明,间充质干细胞从退变的椎间盘渗漏可以导致骨赘形成,因此把向软骨样细胞状态分化的骨髓间充质干细胞进行预处理是有益的。 自体细胞移植具有最低的免疫原性反应,但是这种方法通常受时间的限制,同时需要昂贵的细胞扩增、分化费用,此外体外培养有可能增加感染的概率。有研究人员支持同种异体或异种移植,他们通过椎间盘内部的无血管的性质而认为椎间盘内部组织是无免疫保护 的[25-26]。NOMURA等[27]以兔作为同种异体移植物的捐献者和接受者进行实验,对腰间盘突出症模型兔注射髓核或髓核细胞,并行对照比较,得出结果:同种异体移植物没有诱导任何明显的宿主-移植物反应,且效果优于不治疗。 2.3 临床报告 椎间盘中细胞增殖的潜力有限,许多研究都围绕如何将外源性细胞移植到椎间盘中对其进行修复,这些被移植的细胞可以与椎间盘内的细胞原位结合,不仅有助于产生新的基质而且也可以通过分泌相关因子刺激受体椎间盘细胞分化增殖。HAUFE等[13]研究评估了细胞移植促进椎间盘的再生情况,其对椎间盘源性腰痛患者移植自体造血干细胞治疗,同时进行持续2周的高压氧治疗,随访1年在影像学上观察实验组和对照组没有显著差异。 德国和奥地利的研究人员联合多中心实验评估了细胞移植治疗的疗效,2组患者分为椎间盘切除术组和椎间盘切除术后细胞移植组,与仅椎间盘切除术组相比,细胞移植组术后疼痛的临床评分显著降低[28],2年随访中观察到细胞移植组邻近椎间盘的含水量得到改善,2组椎间盘的高度指数没有显著性差异。 YOSHIKAWA等[29]研究了自体骨髓间充质干细胞的潜能,首先将间充质干细胞输注到真皮胶原海绵中,手术开窗后将移植的胶原海绵插入2例患有椎间盘退变的女性患者椎间盘中。术后2年随访影像学检查显示椎间盘的稳定性增强,此外椎间盘的含水量也显著改善,患者自述腰痛和腿部麻木的临床症状也得到改善。 PETTINE等[30]研究了26例椎间盘源性腰痛伴椎间盘退变的患者,这些患者接受自体骨髓浓缩物(含有多种间充质干细胞)移植治疗,有21例患者的腰痛症状得到持续、显著的改善,其中有8例在1年后Pfirrmann分级有一级改善,研究结果表明移植的效果取决于植入的细胞浓度,而体外间充质干细胞的增殖能力则与患者年龄有关,年龄是决定治疗有效的关键因素之一。 CORIC等[22]把同种异体青少年的软骨细胞经过纤维蛋白基质包裹后,再经皮植入到15例患有单节段腰椎退变合并下腰痛患者的椎间盘中。随访的13例患者中有10例椎间盘的含水量增加,而且没有严重的不良反应。通过残疾指数对所有受试者的疼痛和残疾进行了评估,结果都得到改善,也未见椎间盘高度指数改变。 MOCHIDA等[23]报告了9例Pfirrmann Ⅲ级椎间盘退行性变患者的前瞻性临床研究,通过酶消化回收挤压盘,而后分离出髓核细胞,并将髓核细胞与自体骨髓来源间充质干细胞共培养3 d。在第1次融合手术后7 d,将重新激活的自体髓核细胞移植到融合的椎间盘和附近的椎间盘中。MRI影像学资料显示1例患者症状轻微改善。所有患者在移植后3年的随访中自述腰痛减轻,椎间盘高度指数没有恶化,也未见不良反应。 ELABD等[31]描述了自体骨髓间充质干细胞移植治疗5例患有退行性椎间盘疾病患者,移植前间充质干细胞在缺氧(体积分数为5%O2)条件下进行预处理。所有患者疼痛改善,5例中有4例椎间盘的活动性得到了改善,5例患者均表现为后凸减轻,MRI影像学资料评估显示5例患者中有4例椎间盘高度轻度降低,未观察到椎间盘含水量改变及其他异常。 2.4 移植方法学 由于椎间盘的无血管分布的特性,注射移植目前仍然是唯一的给药途径。然而,注射需要穿刺纤维环进入到椎间盘,这使得椎间盘加速衰老[32]。细胞移植的另一个基本考虑是细胞植入的载体或培养基,大多数研究集中在以各种方式将移植的细胞包裹封装。在这些临床试验中使用的载体是胶原、纤维蛋白、透明质酸和透明质酸衍生物凝胶。凝胶性质和支持作用可以增强原位结合和引导分化。封装也是限制细胞渗漏的一种潜在方法,但是细胞渗漏可能是在移植过程中或原位通过纤维环裂隙时发生,从而使异位骨赘形成。载体也可以被修饰并载入生物活性因子或药物以增强所需的再生过程。另一个要考虑的问题是植入的细胞数量和移植的体积。SERIGANO等[33]在犬椎间盘退行性变模型中的研究表明,细胞疗法的效果取决于移植细胞的数量。这里所提到的所有研究似乎始终坚持单次数量106或107个细胞,而骨髓浓缩物的研究平均植入1.2×108个细胞。虽然目前应用的细胞剂量可以在一定程度上促进下背痛的恢复;但是,目前的研究工作中没有得出最佳的细胞剂量。 2.5 疗效评价 所有已确定的研究是以影像学资料结合自我报告对疼痛和残疾进行评分,这使结果参数受到限制。虽然疼痛和残疾评分的降低是主要的目的,但这些评估并没有直接呈现椎间盘特征的改善。此外,所有的研究都没有纠正安慰剂效应,因此应该谨慎地解释结果。MRI模式仍然是评估椎间盘结构修复的主要方法,通过评估椎间盘高度指数[34]、Pfirrmann分级和强度值来评估修复效果。但是,有报道表明基于MRI分类与组织学特征之间缺乏相关性,且含水量的下降不是椎间盘退变的特有表现,MRI也不能观察到细胞聚集和纤维环裂等特征。因此,成像技术的新进展和临床标准化迫在眉睫,如MR光谱,一种能够直接评估原位基质组成的发展技术。此外,生物标志物领域的进展,如CCL5和CXCL6的发现[35-36],也可能为细胞治疗有效性的评估提供新的、方便的和可靠的参数。 2.6 适应人群的选择 该综述涉及的临床试验的主要目的是为了减轻椎间盘退行性变患者相关的疼痛和残疾。但是,由椎间盘退变引起的疼痛表现仍然存在一些争议。此外,椎间盘退变是由多种因素促进的,如遗传学因素、生活方式、机械因素和衰老[37]。因此,细胞治疗可能为轻度退行性变患者提供更多的预防性机会以阻止向继发性脊柱疾病的发生和发展。 目前现有的研究仍未能确定受益于椎间盘细胞治疗患者群体的选择标准[38]。从临床角度上看,椎间盘基质的轻度改变不能早期从影像学资料上表现出来。对椎间盘退变在基因上研究(遗传易感性)的新见解正在为选择合适的患者进行细胞移植治疗提供新的思路[39]。"
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