Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (41): 6714-6718.doi: 10.3969/j.issn.2095-4344.2014.41.027
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Ruan Guang-ping, Yao Xiang, Liu Ju-fen, Shu Fan, He Jie, Yang Jian-yong, Pang Rong-qing, Pan Xing-hua
Revised:
2014-08-27
Online:
2014-10-01
Published:
2014-10-01
Contact:
Pan Xing-hua, M.D., Chief physician, Stem Cell Engineering Laboratory, Kunming General Hospital of Chengdu Military Region, Kunming 650032, Yunnan Province, China
About author:
Ruan Guang-ping, M.D., Associate chief physician, Stem Cell Engineering Laboratory, Kunming General Hospital of Chengdu Military Region, Kunming 650032, Yunnan Province, China
Supported by:
the National Natural Science Foundation of China, No. 31172170; the National Key Basic Research and Development Program of China (973 Program), No. 2012CB518106; Special Project of High-New Technology Industrial Development in Yunnan Province, No. 201204; National Support Program, No. 2014BAI01B01
CLC Number:
Ruan Guang-ping, Yao Xiang, Liu Ju-fen, Shu Fan, He Jie, Yang Jian-yong, Pang Rong-qing, Pan Xing-hua. Role of human umbilical cord mesenchymal stem cells: cell transplantation, immuoregulation and target cells [J]. Chinese Journal of Tissue Engineering Research, 2014, 18(41): 6714-6718.
2.1 人脐带来源间充质干细胞的特征 2.1.1 人脐带来源间充质干细胞的免疫表型 使用间充质干细胞相关的主要问题是移植后受者的免疫排斥。在异基因细胞来源的细胞治疗中,移植后免疫排斥也是主要问题。实际上,骨髓间充质干细胞的表面免疫遗传标志是低免疫原性的,可以防止异基因淋巴细胞增生[16]。与骨髓间充质干细胞相同,主要组织相容性Ⅱ类分子和共刺激分子,如CD40,CD40配体,CD80和CD86参与到移植排斥的T细胞活化反应中,这些分子在人脐带来源间充质干细胞中不表达,尤其当有丝分裂原或异基因刺激信号传送时。另外,人脐带来源间充质干细胞分化为软骨细胞和神经元样细胞,不引起这些免疫表面分子表达,在体外混合淋巴细胞反应(MLR)不引起异常淋巴细胞增生[17]。对比骨髓间充质干细胞,人脐带来源间充质干细胞显示出更低的免疫原性。事实上,未分化和分化的人脐带来源间充质干细胞可以作为细胞基础治疗,因为允许更大程度HLA误配而没有移植物抗宿主病,而骨髓间充质干细胞则不行。因此,在特定的生物学条件下,人脐带来源间充质干细胞的免疫表型可以保留低免疫原性,显示出良好的干细胞应用前景。 2.1.2 人脐带来源间充质干细胞的免疫调节性质 已知间充质干细胞有免疫抑制功能,在混合淋巴细胞反应中对淋巴细胞增生有抑制作用,通过同种抗原和有丝分裂原,比如应用植物血凝素来减少促炎因子水平。最近证据表明人脐带来源间充质干细胞不仅抑制成熟树突状细胞功能,而且增加与免疫调节相关的调节性T细胞的百分比[18]。间充质干细胞调节免疫反应是通过可溶因子和细胞与细胞之间联系机制介导的。目前,参与免疫抑制的可溶因子包括转化生长因子β等[19]。实际上,一些数据表明,人脐带来源间充质干细胞促进前列腺素E2、吲哚胺2,3双加氧酶等细胞因子的分泌,调节单核巨噬细胞、T细胞、B细胞、NK细胞等免疫细胞的增殖、分化和功能。另外,HLA-G分子在免疫耐受状态的形成及维持中具有重要作用,有研究通过荧光活化细胞分选分析在人脐带来源间充质干细胞中检测到HLA-G表面分子[20]。 因此,利用人脐带来源间充质干细胞的免疫调节性质,并应用于治疗许多人类免疫学疾病,还要进一步研究。 2.2 在疾病模型中应用人脐带来源间充质干细胞 2.2.1 人脐带来源间充质干细胞用于软骨再生 间充质干细胞来源于中胚层,具有高度自我更新能力,几个研究组尝试用间充质干细胞治疗骨性关节炎和类风湿性关节炎。骨关节炎的主要特征包括有软骨退行性病变和关节边缘骨赘的形成,其发病原因及发病机制尚不十分明确,可能与年龄增长、过度使用、损伤、肥胖、遗传等多种因素密切相关。类风湿性关节炎是慢性自身免疫疾病,主要特征为滑膜或关节炎症引起长期关节损伤[21]。人脐带来源间充质干细胞在中胚层分化潜能中有更高的向软骨分化的能力,有望用于治疗软骨组织损伤及退变性疾病。最近的进展证明间充质干细胞显示了潜在的免疫抑制和抗炎症效应,可能与其特异地分泌一些细胞因子和生长因子有关,例如血小板因子1,2作为类风湿性关节炎中抗炎症因子,通过抑制产生促炎介导剂比如γ-干扰素和肿瘤坏死因子α,清除滑膜残存T细胞,减少单核细胞/巨噬细胞在关节组织的浸润[22]。以这种方式,软骨分化和旁分泌作用参与到替代损伤的软骨组织,刺激再生过程。 然而,几个研究团队进行了研究,证明了骨髓间充质干细胞对骨性关节炎或类风湿性关节炎的治疗潜能[23-24],但还没有研究报道人脐带来源间充质干细胞的治疗潜能。人脐带来源间充质干细胞修复和再生软骨的机制和分子机制仍然未被深入研究。现在有一些临床Ⅰ/Ⅱ期的结果支持(NCT01041001),通过充分理解软骨退变疾病重要的再生机制,调整最佳的人脐带来源间充质干细胞治疗条件,有理由相信可以用人脐带来源间充质干细胞治疗软骨退变疾病。 2.2.2 人脐带来源间充质干细胞用于神经胶质瘤 间充质干细胞可以直接作用肿瘤细胞,抑制其生长,并能特异性迁移到损伤部位和肿瘤组织[25],传递和表达多种抗种瘤因子,诸多研究将间充质干细胞作为诱导肿瘤细胞凋亡、抑制肿瘤细胞分化、抑制肿瘤血管生成药物的载体,并取得了显著抗肿瘤效果。利用间充质干细胞作为特异的载体,携带白细胞介素、干扰素、趋化因子、肿瘤坏死因子、生长因子拮抗剂等抗肿瘤因子,迁移到肿瘤部位,可杀伤或抑制肿瘤细胞生长。分泌TRAIL的人脐带来源间充质干细胞在颅内神经胶质瘤模型显示出了治疗效果[26]。注射间充质干细胞能抑制肿瘤生长,延长神经胶质瘤鼠的生存期。研究者在人脐带来源间充质干细胞迁移到胶质瘤时检测了白细胞介素8的变化,高水平的白细胞介素8在共培养胶质瘤细胞和人脐带来源间充质干细胞的条件培养基中被检测到。在Transwell系统中过表达重组白细胞介素8的人脐带来源间充质干细胞发生了增强迁移,当用抗CXC趋化因子受体1的抗体(白细胞介素8受体)预处理人脐带来源间充质干细胞时,迁移的效果发生了减弱。因此,以间充质干细胞为载体,靶向递送白细胞介素8来治疗胶质瘤的方法备受关注[27],可以期望白细胞介素8受体在人脐带来源间充质干细胞过表达,将有效传送癌症药物到达胶质瘤。脐带间充质干细胞可能有潜力作为治疗脑胶质瘤基因靶向治疗的细胞载体,但应该建立更有效安全的治疗方法。 2.2.3 人脐带来源间充质干细胞用于缺血脑损伤 因为缺血引起的脑损伤不能恢复,会导致严重的脑功能缺陷[28]。有关人脐血干细胞治疗效果的第一个证据来自Chopp实验室,采用大脑中动脉栓塞诱导局部缺血,然后静脉内注射人脐血单个核细胞可以减少大鼠脑缺血后的行为缺陷[29]。最近报道在比格犬脑缺血后1 d通过血管介入方法移植人脐带来源间充质干细胞,1周后梗死体积明显减小,移植的人脐带来源间充质干细胞能分化成神经元和星形胶质细胞,在移植后4周可分泌神经保护因子,如脑源性神经营养因子和血管内皮生长因子[30]。Jeong等[31]报道移植人脐带来源间充质干细胞到脑损伤后7 d大鼠,可发生有意义的行为改善。另外,移植后4周PKH26标记的人脐带来源间充质干细胞在损伤侧分化成神经细胞。这些结果表明移植人脐带来源间充质干细胞可以用在脑缺血的研究中。用人脐带来源间充质干细胞进行治疗的关键仍是移植途径和移植时间。 2.2.4 人脐带来源间充质干细胞用于肺疾病 急性呼吸窘迫综合征(ARDS)是指肺内、外严重疾病导致以肺毛细血管弥漫性损伤、通透性增强为基础,以肺水肿、透明膜形成和肺不张为主要病理变化,以进行性呼吸窘迫和难治性低氧血症为临床特征的急性呼吸衰竭综合征。人脐带Wharton胶来源干细胞表型与间充质干细胞一致,被用来治疗用博来霉素诱导的肺损伤鼠模型[32]。2周后,移植的人脐带来源间充质干细胞定位在炎症和纤维化区。注射人脐带来源间充质干细胞会减少炎症反应,抑制转化生长因子β,γ-干扰素和促炎细胞因子的表达,包括巨噬细胞迁移抑制因子和肿瘤坏死因子α。而且,肺中胶原水平显著下降,可能是因为上调了基质金属蛋白酶2水平和下调了基质金属蛋白酶组织抑制剂水平。这些结果表明人脐带来源间充质干细胞参与了肺损伤中的抗纤维化作用。有趣的是,在免疫功能正常的新生大鼠,人脐带来源间充质干细胞移植减轻了高氧诱导的肺损伤[33]。在出生后5 d Sprague-Dawley大鼠给予单剂量的PKH26标记的人脐带来源间充质干细胞通过气管(2×106个细胞)或腹膜(5×105个细胞)给药,评估人脐带来源间充质干细胞的免疫调节和分化潜能,结果表明高氧诱导增加死亡细胞的数量、髓过氧化物酶活性以及肺泡异常,随着气管内给予人脐带来源间充质干细胞,白细胞介素6 mRNA水平明显降低,而且肿瘤坏死因子α,转化生长因子β mRNA,α-SMA蛋白和胶原由于人脐带来源间充质干细胞的作用有意义的减少了。在肺损伤组织内观察到PKH26标记分化的肺泡上皮细胞,可见人脐带来源间充质干细胞具有抗炎和再生作用,可以被用来治疗高氧诱导的肺损伤。 2.2.5 人脐带来源间充质干细胞用于肝疾病 肝纤维化是持续肝损伤的结果,纤维化会不断地发展,肝脏在遭受持续性损伤后,正常的肝组织就会被纤维组织所替代形成肝纤维化。引起肝纤维化的病因有很多,通常由酒精肝、脂肪肝、乙肝和丙肝病毒引起,当前没有有效的治疗手段。最近报道表明间充质干细胞可诱导分化为肝细胞,在四氯化碳诱导的大鼠纤维化模型内,人脐带来源间充质干细胞输注可以抑制转化生长因子β1,Ⅰ型胶原和α-SMA的表达。另外,在损伤的肝内可见CM-DiI-标记的人脐带来源间充质干细胞表达肝细胞特异标志白蛋白和α-甲胎蛋白。Yan等[34]也观察到相同结果。有趣的是,终末脱氧核苷酸转移酶介导的脱氧尿苷三磷酸(dUTP)生物素缺口末端标记和增生的细胞核抗原染色表明,移植的人脐带来源间充质干细胞能防止肝细胞死亡和刺激增生。当前难于决定哪种干/前体细胞群对肝疾病治疗是最好的。 2.2.6 人脐带来源间充质干细胞用于心肌梗死 介入技术的普及延长了心肌梗死患者的生存期,但由于坏死的心肌细胞不能再生,心肌梗死后引起的心力衰竭仍然严重影响着患者的生存质量。研究表明人脐带间充质干细胞有向心肌细胞分化的潜能,与近年来研究较多的骨髓间充质干细胞在移植治疗方面有很多相同特征,且细胞更原始、来源更广泛,无伦理学争论,为心肌细胞移植的理想干细胞来源。HLA-G在移植免疫中的抑制作用一直被中外学者热切关注,且作为一个免疫抑制分子参与间充质干细胞的免疫抑制效应,已得到证实。其蛋白表达特点为:在胎盘形成期,即早孕及妊娠四五个月时强表达,胎盘形成后即弱表达或不表达。研究者通过移植不同月龄有HLA-G表达差异的人脐带间充质干细胞,探讨HLA-G在兔急性心肌梗死血运重建影响中的可能机制[35]。实验为人脐带间充质干细胞移植临床治疗心肌梗死提供了一定的理论和实验依据。结果显示:HLA-G在小月龄组人脐带间充质干细胞中表达强阳性,在足月组人脐带间充质干细胞中表达弱阳性或阴性。分别在兔心肌梗死模型上移植小月龄组人脐带间充质干细胞及足月组人脐带间充质干细胞,4周后可在心肌梗死区域发现标记的间充质干细胞。统计结果表明,相比于对照组,两组人脐带间充质干细胞均能显著减少心肌梗死面积(P < 0.01),而相比于足月人脐带间充质干细胞组,小月龄组人脐带间充质干细胞更能显著促进梗死区新生毛细血管的生成,降低心肌纤维化程度,缩小心肌梗死面积(P < 0.05),提示HLA-G含量较多的小月龄人脐带间充质干细胞能成为心肌细胞移植更理想的来源。"
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