null

doi:10.3969/j.issn.2095-4344.2013.01.026

Abstract

CLC Number:

R318

Xu Zhi-juan, Ouyang Gui-fang. null[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(1): 161-166.

2.1 脐血移植的优缺点与骨髓移植相比，脐血具有如下特点：①来源丰富，收集过程相对简单，对产妇和新生儿不会造成痛苦和不良影响。②不涉及社会、法律及伦理等方面的争论。③由于胎盘屏障的保护，其被病毒、细菌等污染的机会低[4]。④免疫原性弱，移植后较少发生移植物抗宿主病[5]。⑤脐血可以冷冻和储存，需要时即可用，可以消除复杂的骨髓收集所带来的时滞性和不确定性。⑥脐血库中的HLA基因型不会丢失等[6]。因此脐血逐渐成为临床上造血干/祖细胞与间充质干细胞的重要来源[7-8]。但是脐血移植也存在缺点[6]：①单份脐血所含的单个核细胞数量有限，一般只能满足体质量小于或等于30 kg的儿童移植，而较大儿童或成年人则由于数量不足而受到限制[9]。②与骨髓移植相比移植物植入失败率高。③植入受者体内的潜在异常的新生儿供体造血干细胞对受者的影响在移植时是未知的。近年来发展的造血干细胞体外扩增技术，有望可以在短时间内扩增造血干细胞，满足临床上造血干细胞移植的需要。然而，研究发现虽然造血干细胞具有很好的扩增效应，但移植入体内的效果却令人不满意，这是因为造血干细胞在体外经细胞因子作用后，常常发生过度分化，以至于难以维持干细胞的性能。因此，继续寻找更有效的体外扩增手段，使造血干细胞在体外大量扩增，同时保留造血干细胞的功能活性，成为研究中要解决的关键问题。骨髓是造血干/祖细胞的主要发源地，体内的稳态造血有赖于完整的造血微环境，主要通过骨髓内基质细胞产生的生长或抑制因子、细胞与细胞间的相互作用以及细胞基质与造血细胞间的相互作用来调节造血功能。间充质干细胞是造血微环境中重要的基质细胞前体细胞[10-11]，通过与造血干细胞直接接触、分泌多种细胞因子及细胞外基质等维持造血微环境结构和功能的完整性，进而实现对造血的精细调控[12-13]，郝牧等[14]的研究结果显示间充质干细胞与造血干细胞在体外培养时，能明显扩增造血干细胞并能够维持其生物学特性。体外培养时间充质干细胞能分泌多种造血因子，并且能表达多种与造血相关的黏附因子，在造血调控中具有重要作用[15]。目前骨髓间充质干细胞应用于造血干/祖细胞移植的研究和临床结果令人备受鼓舞[16-19]，但是骨髓间充质干细胞来源受限、且随着年龄的增长其分化潜能逐渐降低，使其广泛应用在一定程度上受到限制[20]。而脐血源性间充质干细胞取材方便，具有更高的增殖和分化潜能，且来源于胚胎组织，免疫原性较骨髓间充质干细胞低[21]，使其在造血干细胞移植后的促造血重建方面具有更大的应用空间。 2.2 脐血间充质干细胞支持造血作用 2.2.1 脐血间充质干细胞分泌多种具有造血支持作用的细胞因子造血因子对于造血干细胞的扩增和增殖是必不可少的。Jang等[22]在造血细胞存在而无分化刺激的培养条件下培养间充质干细胞，并对脐血和骨髓源性间充质干细胞进行比较，通过RT-PCR和免疫印迹分析检测造血相关因子的表达，结果表明脐血和骨髓源性间充质干细胞共同表达白细胞介素1α、6和7，白血病抑制因子，FL，干细胞因子，巨噬细胞集落刺激因子和C-kit。但值得注意的是，通过RT-PCR检测白细胞介素1β和粒细胞-巨噬细胞集落刺激因子只在脐血源性间充质干细胞中表达。且此结果得到免疫印迹分析证实。这些结果表明，尽管脐血和骨髓源性间充质干细胞造血相关细胞因子表达谱相似，但是脐血源性间充质干细胞可能通过其表达的独特的细胞因子如白细胞介素1β和粒细胞-巨噬细胞集落刺激因子，而具有不同的作用或活性。 Yim等[23]将脐血间充质干细胞与CD34+造血干细胞由静脉共同输注至NOD/SCID小鼠体内，发现间充质干细胞有助于造血干细胞植入；同时检测出脐血间充质干细胞可分泌具有支持造血作用的干细胞因子和基质细胞衍生因子1。Noh等[24]报道脐血间充质干细胞可分泌与造血干细胞植入和归巢相关的chemokine ligand 12(CXCL12)、上皮生长因子、干细胞因子等，并认为可提高造血干细胞植入和归巢效力。Ryu等[25]研究显示脐血间充质干细胞能够分泌化学趋化因子，并表达其受体CXCR4引导造血干细胞归巢，从而促进其有效植入。Huang等[26]将脐血间充质干细胞与造血干细胞共同培养，发现脐血共同培养组与对照组相比CD34+细胞扩增能力增加，长期培养启动细胞，粒巨噬细胞集落形成细胞和高增殖潜力集落形成细胞均优于对照组。此外，间充质干细胞还表达CD34+造血干/祖细胞向巨核细胞和血小板前体细胞分化相关的细胞因子。巨核细胞和血小板的生成有赖于造血干细胞、骨髓基质细胞和体液因子的相互作用。Cheng等[27]发现体外培养的间充质干细胞除表达白细胞介素6，7，8，11，12，14，15、巨噬细胞集落刺激因子、FL和干细胞因子等因子外，还表达调节巨核细胞生成的基本因子血小板生成素的mRNA。在骨髓微环境中可提供刺激CD34+造血细胞向巨核细胞分化和生成血小板关键的信号。 2.2.2 间充质干细胞表达的与造血细胞相互作用的黏附分子造血微环境对造血细胞的自我更新、定向分化、增殖及造血细胞在骨髓中滞留定位有重要作用。造血细胞与基质细胞的黏附对造血调控至关重要，细胞黏附分子在造血细胞的植入和归巢中起着重要的作用。黏附分子是一类介导细胞与细胞之间、细胞与细胞外基质之间黏附作用的膜表面糖蛋白，主要包括选择素家族、免疫球蛋白超家族、整合素家族、钙依赖黏附素家族以及CD44分子等。在造血干细胞归巢过程中黏附分子介导的细胞与细胞间、与细胞外基质间的相互作用发挥着重要的作用。造血干细胞表达多种黏附分子包括：①L-selectin(L-选择素、CD62L)，受体为内皮细胞表面的CD34，二者相互结合可介导造血干细胞与内皮细胞可逆接触，并使LFA-1的亲和性增高。②整合素α4β1(CD49d/CD29、VLA-4)，与L-selectine协同促进造血干细胞归巢，与VCAM-1和纤维粘连蛋白结合后使造血干细胞迁移速度加快，对造血干细胞到达骨髓微环境后的锚定和重建造血有非常重要的作用。③整合素α5β1(CD49e/CD29、VLA-5)，与纤维粘连蛋白结合介导造血干细胞的黏附和定向迁移。④整合素αLβ2(CD11a/CD18、LFA-1)，与细胞间黏附分子1结合对造血干细胞在造血微环境中稳定黏附、穿过内皮和迁移起重要作用。⑤ALACM(CD166)，在造血干细胞、间充质干细胞和内皮细胞均有表达，介导ALACM-CD6/ALACM-ALACM之间的细胞黏附作用，并参与造血干细胞与基质细胞的结合，维持造血干细胞的多向分化潜能并支持其增殖。⑥HCAM (CD44)，与细胞外基质透明质酸结合支持造血干细胞的黏附、增殖和分化，用抗体阻断其功能后造血干细胞归巢和植入彻底中断。⑦PECAM(CD31)，在造血干细胞穿过内皮细胞及其迁移过程中发挥重要的作用。间充质干细胞作为造血微环境基质细胞的前体细胞，既能分泌造血调控因子又能选择性黏附并支持CD34+造血细胞分化和增殖，表达大量的表面标志物，大部分是黏附因子，在与造血细胞的相互作用中发挥重要作用[28]，如黏附分子ALCAM、ICAM-1、ICAM-2、ICAM-3、LFA-3、PECAM-1、VCAM，选择素家族selectin-E、selectin-L、selectin-P，透明质酸受体CD44、纤维连接蛋白受体、胶原蛋白受体，生长因子和细胞因子受体IL-1R、IL-2R、IL-4R、IL-6R、IL-7R、TNF-α-1R、TNF-α-2R、FGFR、PDGFR，整合素家族VLA-α1、VLA-α2、VLA-α3、VLA-α4、VLA-α5、VLA-α6、VLA-β、integrinβ4，transferrin受体、cadherin 5、Thy-1。霍思维等[29]的实验结果也证实间充质干细胞稳定表达多种细胞黏附分子，如整合素β1、整合素α5、VCAM-1、ICAM-1、ICAM-2、ICAM-3等，这些黏附分子在造血干细胞分化、增殖、归巢过程中有着重要的作用，提示间充质干细胞具有造血调控作用。同时也探讨了间充质干细胞对CD34+细胞的迁移作用，在Transwell共培养体系中，CD34+细胞的迁移率随着下腔间充质干细胞密度的增加而增加，以2×104间充质干细胞时CD34+细胞迁移率最高，且间充质干细胞对CD34+细胞的迁移作用远大于单一趋化因子。 2.2.3 间充质干细胞支持造血干细胞体外扩增足够数量的造血干细胞是造血干细胞移植成功的必需条件。所以造血干细胞体外扩增日益受到重视。长期的造血细胞培养依赖于可溶性细胞因子包括粒-巨噬细胞集落刺激因子、粒细胞集落刺激因子、干细胞因子、白血病抑制因子、巨噬细胞集落刺激因子、FLK-2如前所述，间充质干细胞能分泌多种造血相关细胞因子，从而有效支持造血干细胞体外扩增。为探讨脐血来源的间充质干细胞是不能支持CD34+细胞体外扩增。Jang等[22]在不同的环境下培养CD34+细胞，结果显示以脐血间充质干细胞、骨髓间充质干细胞为饲养层培养的CD34+细胞较单纯以细胞因子培养的CD34+细胞细胞总数分别增长至(15.2±2.5)×105和(8.6±0.8)×105。说明脐血间充质干细胞体外扩增CD34+细胞能力较骨髓间充质干细胞及细胞因子强。Jang等[22]进一步研究脐血间充质干细胞体外扩增能力，将人脐血间充质干细胞作为滋养层，在不添加任何细胞因子的情况下，人脐血来源的造血干/祖细胞所形成的巨噬、粒细胞集落形成单位，巨噬、粒、红细胞、巨核细胞集落形成单位，红细胞集落形成单位以及红细胞爆式集落形成单位的出现频率分别增加至3.46倍、9.85倍、2.03倍、3.64倍。Kedong等[30]报道将脐血间充质干细胞与造血干细胞共同培养12 d，集落形成单位与造血干细胞分别扩增(5.1±1.2)与(5.2±0.4)倍。 2.2.4 联合移植间充质干细胞对造血重建有促进作用联合移植间充质干细胞和造血干细胞可提高造血干细胞移植成功率。周敦华等[31]的实验结果显示，CD34+细胞(低细胞量移植组1×105/只和高细胞量移植组1×106/只)，联合移植组同时输注脐血间充质干细胞(1×106/只)移植入NOD/SCID小鼠体内，同时单纯移植组作为对照，观察到①低细胞量移植时，CD34+植入率联合移植组明显高于单纯移植组；高细胞量移植时，单纯移植组和联合移植组的植入率相近。②低细胞量移植时，联合移植组和单纯移植组的存活率分别为70%和50%；高细胞量移植时，联合移植组和单纯移植组的存活率分别为80%和70%；间充质干细胞与CD34+细胞联合移植时可提高小鼠存活率，低细胞量移植时更明显。③联合移植小鼠白细胞、血小板和血红蛋白的恢复明显早于单纯移植组。④间充质干细胞联合移植可促进人脐血CD34+细胞在NOD/SCID小鼠体内向粒系、B淋巴系和巨核系定向分化。Hao等[32]将间充质干细胞(5×106/只)与CD34+细胞(5×105/只)共同移植入放射线照射后的NOD/SCID小鼠，CD34+细胞(5×105/只)单独移植作为对照组，移植20 h后用流式细胞术在小鼠骨髓和脾脏中检测人CD45+细胞，结果显示共移植组CD34+细胞骨髓归巢率[(7.2±1.1)%]高于单移植组[(5.4± 0.9)%，P < 0.05]；共移植组CD34+细胞迁移率[(35.7±5.8)%]明显高于对照组[(3.5±0.6)%]；CD34+细胞与间充质干细胞共培养组培养4 d和7 d时CD49e、CD31、CD62L的表达明显高于CD34+细胞单培养组，说明间充质干细胞有促进CD34+细胞表面归巢黏附分子表达的作用。 2.2.5 其他虽然目前大多数体外实验结果都显示间充质干细胞支持造血的主要方式是产生细胞因子和黏附分子等基质成分[33-34]，但是间充质干细胞与造血干/祖细胞直接密切接触并通过细胞间的信息传递可能也是其支持造血的重要方式。在体外脐血源性间充质干细胞与造血干细胞共培养时观察到的鹅卵石样造血形成区，提示间充质干细胞与造血干细胞密切接触也有利于造血干细胞的增殖与分化[35]，其具体机制有待于进一步研究。"

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