How to improve mesenchymal stem cells theropy for Duchenne muscular dystrophy?

doi:10.3969/j.issn.2095-4344.2015.01.025

Chinese Journal of Tissue Engineering Research ›› 2015, Vol. 19 ›› Issue (1): 140-145.doi: 10.3969/j.issn.2095-4344.2015.01.025

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How to improve mesenchymal stem cells theropy for Duchenne muscular dystrophy?

Zhu Hui^{1, 2}, Pang Rong-qing¹, Pan Xing-hua¹, Ruan Guang-ping¹

1Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Area of Chinese PLA, Cell Biological Medicine Integrated Engineering Laboratory of State and Regions in Yunnan Province, Stem Cell Engineering Laboratory of Yunnan Province, Transfer medicine Key Laboratory of Cell Therapy Technology of Yunnan Province, Key Laboratory of Stem Cells and Regenerative Medicine of Kunming City, Kunming 650032, Yunnan Province, China
2Kunming Medical University’s Clinical College in Kunming General Hospital of Chengdu Military Region, Kunming 650032, Yunnan Province, China

Revised:2014-09-20 Online:2015-01-01 Published:2015-01-01
Contact: Pang Rong-qing, M.D., Associate chief physician, Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Area of Chinese PLA, Cell Biological Medicine Integrated Engineering Laboratory of State and Regions in Yunnan Province, Stem Cell Engineering Laboratory of Yunnan Province, Transfer medicine Key Laboratory of Cell Therapy Technology of Yunnan Province, Key Laboratory of Stem Cells and Regenerative Medicine of Kunming City, Kunming 650032, Yunnan Province, China
About author:Zhu Hui, Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Area of Chinese PLA, Cell Biological Medicine Integrated Engineering Laboratory of State and Regions in Yunnan Province, Stem Cell Engineering Laboratory of Yunnan Province, Transfer medicine Key Laboratory of Cell Therapy Technology of Yunnan Province, Key Laboratory of Stem Cells and Regenerative Medicine of Kunming City, Kunming 650032, Yunnan Province, China; Kunming Medical University’s Clinical College in Kunming General Hospital of Chengdu Military Region, Kunming 650032, Yunnan Province, China
Supported by:
the Reserve Personnel Training Fund for Young Academic and Technology Leaders of Yunnan Province, No. 2011HB050; the Natural Science Foundation of Yunnan Province, No. 2013DA004; the Science Foundation of Chengdu Military Region, No. B12021; the Medical Outstanding Talent Culture Foundation of Chengdu Military Region, No. 2012WJ003

Abstract

Abstract:

BACKGROUND: Treatment of Duchenne muscular dystrophy is not ideal. In recent years, more and more scientists try to treat Duchenne muscular dystrophy with mesenchymal stem cells.
OBJECTIVE: To summarize the mesenchymal stem cell treatment for Duchenne muscular dystrophy and guide relevant animal experiments in order to promote its clinical application.
METHODS: A computer-based online search of CNKI and PubMed between January 2005 and June 2014 was performed to search related articles with the keywords of “Duchenne muscular dystrophy, mesenchymal stem cells, stem cell transplantation” in English and Chinese, respectively. Literatures related to mesenchymal stem cells for treatment of Duchenne muscular dystrophy were selected; in the same field, the articles published lately in authoritative journals were preferred.
RESULTS AND CONCLUSION: A total of 317 literatures were primarily selected, and 41 articles were involved in result analysis according to inclusion criteria. Mesenchymal stem cells for treatment of Duchenne muscular dystrophy are mainly by increasing the number of homing cells and expression of dystrophin. Common methods are selecting the ideal seed cells, cell pretreatment, improving migration ways and intervening homing process. Mesenchymal stem cells treatment that has broad application prospects is an essential way for the treatment of Duchenne muscular dystrophy, and it can avoid the side effects of drug therapy.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

全文链接：

Key words: Mesenchymal Stem Cells, Mesenchymal Stem Cell Transplantation, Muscular Dystrophy, Duchenne

CLC Number:

R318

Zhu Hui, Pang Rong-qing, Pan Xing-hua, Ruan Guang-ping . How to improve mesenchymal stem cells theropy for Duchenne muscular dystrophy?[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(1): 140-145.

Figures/Tables 1

2.1 杜氏肌营养不良症的临床表现及发病机制杜氏肌营养不良症患儿出生时有血清肌酸激酶(creatine kinase，CK)增高和肌纤维坏死，但身高和体质量均正常，没有明显临床症状。通常因2-5岁出现易跌跤、爬楼和起立困难等情况就诊。多数患儿12岁左右丧失行走能力，20-30岁时呼吸变浅、咳嗽无力，并发肺部感染或心力衰竭而死亡。患儿肌电图和肌肉病理检查均表现为典型的肌源性损害，生化检测显示肌酶谱明显升高，尤其是肌酸激酶大幅升高具有重要的临床诊断价值。杜氏肌营养不良症是由于位于X染色体上的dystrophin基因突变或缺失导致的遗传病。Dystrophin蛋白位于肌细胞膜上，与肌纤维膜糖蛋白结合为抗肌萎缩蛋白复合体，这些蛋白与肌细胞的黏附蛋白联结，构成细胞支架，共同维持着肌纤维的稳定[3]。杜氏肌营养不良症患者由于dystrophin缺失造成细胞骨架不稳定，不能有效抵抗肌纤维的收缩牵拉，其结果是细胞膜通透性发生改变，肌纤维断裂、变性或坏死。肌纤维变性或坏死必然伴随着明显的炎症反应，大量炎性细胞浸润，脂肪及结缔组织增生，患者表现为肌无力症状，腓肠肌明显肥大。所以，杜氏肌营养不良症又称假肥大型肌营养不良症。 2.2 间充质干细胞的生物学特性及功能间充质干细胞广泛存在于骨髓、脂肪、脐带、羊膜等多种组织，具有自我更新和多向分化潜能，最早由Friedenstein等[4]采用贴壁黏附培养方法从骨髓中分离发现。目前，国际细胞治疗协会提出了确定间充质干细胞的标准包括[6]：①体外培养时具有贴壁生长的特性。②表达CD29、CD44、CD71、CD90、CD105、CD166等间质细胞抗原标志，而不表达CD34、CD45等造血细胞抗原标志。③可在体外一定诱导培养条件下分化为成骨细胞、脂肪细胞和软骨细胞。这些评判标准的提出对间充质干细胞的应用研究发挥了重要作用，但由于间充质干细胞没有特异的抗原标志，纯化间充质干细胞尚存困难，究竟哪些细胞属于真正意义上的间充质干细胞也尚存争议[7]，比如骨髓来源表达胚胎干细胞部分抗原标志的贴壁生长细胞是不是间充质干细胞？目前，间充质干细胞的部分生物学特性已经比较明确[8]，主要包括：①自我更新：间充质干细胞可以不对称的减数分裂方式增殖生长。②分化潜能：在特定的微环境条件下，间充质干细胞可以向脂肪、软骨、骨、肌肉等成熟组织细胞分化，这个特性奠定了间充质干细胞在再生医学中应用的重要基础。③免疫调节：间充质干细胞不表达MHC-Ⅱ，CD40和CD80等共刺激分子[9]，可以抑制淋巴细胞的增殖反应，这个特性使得间充质干细胞可进行异体甚至异种移植而不发生免疫排斥反应[10]，即间充质干细胞具有低免疫原性。④旁分泌功能[11]：间充质干细胞本身可分泌细胞因子、营养因子等多种因子，这些因子参与机体免疫调控、抗炎治疗和组织的修复与再生。⑤归巢特性：间充质干细胞具有向损伤组织靶向迁移的生物学特性，与趋化因子密切相关。以此生物学特性为基础，间充质干细胞用于杜氏肌营养不良症治疗可能通过至少5种机制发挥作用：①直接分化机制[12]：间充质干细胞可在体外诱导环境下和体内微环境条件下分化为肌细胞。②内源细胞生长机制[13]：植入体内的干细胞可分泌多种细胞生长因子促进内源性肌细胞的生长增殖而参与组织损伤的修复。③血管再生机制[14-15]：植入体内的干细胞可向内皮细胞分化而再生血管，血管的再生改善了血液循环、促进了组织的修复。④免疫调节机制：注入体内的间充质干细胞可通过抑制T淋巴细胞增殖和促炎因子的产生而减缓肌纤维坏死引发的炎症反应[16]。⑤细胞融合机制[17]：干细胞进入组织后，与现存的肌细胞发生融合，形成成熟的细胞。 2.3 间充质干细胞移植治疗杜氏肌营养不良症进展及存在的问题杜氏肌营养不良症患者之所以发病，关键原因在于dystrophin蛋白缺失导致肌纤维不稳定而坏死。因此，干细胞移植不失为治疗杜氏肌营养不良症的良好选择。干细胞移植治疗杜氏肌营养不良症的基本原理就是通过把健康供者来源的干细胞输入到杜氏肌营养不良症患者体内以重建dystrophin蛋白的表达。在此原则指引下，干细胞治疗杜氏肌营养不良症取得了以下进展，主要包括：①间充质干细胞可以诱导分化为肌细胞：不同物种来源的间充质干细胞可在一定培养条件下分化为多核的肌管，并表达肌细胞特有的抗原标志[18]。目前认为间充质干细胞定向分化为骨骼肌细胞可能存在两种机制：第一种是供者细胞受到肌纤维变性坏死信号的趋化作用迁移到受损肌肉组织并最终分化成熟、融合入变性的肌纤维或者形成新的肌纤维；第二种则是供者间充质干细胞向卫星细胞分化从而进一步促进肌肉再生。供者健康的间充质干细胞可分化为有dystrophin表达的肌细胞。②间充质干细胞可在体内重建dystrophin蛋白的表达：以静脉输注方式异体移植甚至异种移植间充质干细胞到杜氏肌营养不良症动物模型体内，可以检测到植入间充质干细胞来源的dystrophin蛋白的表达，并能观察到杜氏肌营养不良症模型动物临床症状的改变[19]。③临床试验表明：以静脉输注方式移植异体间充质干细胞给杜氏肌营养不良症患者，可以降低患者异常升高的外周血肌酸激酶含量，提高杜氏肌营养不良症患者上下肢肌力[5，20]。这些研究证实间充质干细胞可用于杜氏肌营养不良症的治疗，然而归巢间充质干细胞数量少，dystrophin表达量少(间充质干细胞移植入mdx鼠后16周dystrophin阳性的肌纤维占15% [10])，重建和修复肌细胞的程度不足以满足患者日常活动肌力所需正常肌细胞数量是限制间充质干细胞治疗杜氏肌营养不良症疗效的关键问题。 2.4 提高间充质干细胞治疗杜氏肌营养不良症疗效的努力方向干细胞移植有效治疗杜氏肌营养不良症的关键是重建dystrophin蛋白的表达，不同间充质干细胞可能生物学特性不同，移植后可能产生不同的治疗效果，从间充质干细胞生物学特性出发，干细胞治疗杜氏肌营养不良症仍有很大的改进提高空间。 2.4.1 种子细胞的选择间充质干细胞来源的选择：间充质干细胞可从多种组织分离获得，其基本生物学特性类似，但不同组织来源的间充质干细胞旁分泌因子不同，年轻组织来源细胞增殖和再生能力较强[21]。作为杜氏肌营养不良症治疗的种子细胞，间充质干细胞最好从年轻组织分离获取。比如脐带，它属于胎儿的附属组织，从脐带获得的细胞增殖能力强，活性较好，不像骨髓来源的间充质干细胞往往受供者年龄限制。而且，从脐带组织分离获取间充质干细胞属于变废为宝的行为，取材无伤痛，不涉及伦理问题，可一次获得大量细胞，且容易进行标准化生产[22]，用于杜氏肌营养不良症治疗效果会更好。间充质干细胞分离方法的优化：通常认为间充质干细胞表达CD29、CD44、CD90、CD105等间充质抗原标志，具有分化的多能性，而胚胎干细胞表达Oct-4、Nanog-3和SSEA-1(4)等多潜能抗原标志，具有分化的全能性。近年来多个实验小组从骨髓、胎盘等组织中都分离到了与间充质干细胞形态特征类似的细胞，但这些细胞表达Oct-4、Nanog-3和SSEA-1(4)等抗原标志，被命名为胚胎样干细胞(embryonic-like stem cells)或很小的胚胎样干细胞(very small embryonic-like stem cells，VSEL-SC)等[23-25]。这些细胞被认为是胚胎发育过程中遗留下来处于静息状态的原始干细胞，是组织再生真正意义上的干细胞，具有最大的再生能力[7]。通常采用一些有利于保持干细胞干性的培养方法分离获得这些细胞，以便最大限度地保持这些细胞的再生潜能[26]。此外，间充质干细胞反复传代会导致其干性丢失，影响其治疗效果[27]。因此，筛选优化间充质干细胞的分离培养方法是提高间充质干细胞治疗杜氏肌营养不良症疗效的一个重要切入点。 2.4.2 间充质干细胞的预处理获得间充质干细胞后，将其与galectin-1共培养3 d后再移植给mdx鼠，可以提高4倍的肌纤维再生效率，培养3 d即可检测到MyoD基因的表达，galectin-1是MyoD基因成肌调节因子成员之一，主要在成肌细胞分化早期起决定作用[18]。这表明间充质干细胞预处理(即与成肌诱导因子短暂培养)是提高间充质干细胞治疗效率的有效手段。间充质干细胞体外预处理的本质是增加MyoD等命运决定基因表达的概率，增加间充质干细胞成肌分化的效率。 2.4.3 细胞移植方法的选择静脉输注是临床上常用的给药途径。采用静脉移植间充质干细胞，具有创伤小、易被患者接受、细胞能够到达全身的优点。无论是骨骼肌、膈肌，静脉移植间充质干细胞后都能在这些肌肉组织检测到植入细胞来源的肌纤维，但临床上常用的静脉穿刺点是上肢表浅静脉，细胞进入血管后必须随着血液循环才能到达远端病灶，一方面细胞广泛分布稀释了到达骨骼肌、膈肌的细胞浓度，另一方面进入机体的间充质干细胞并非全身分布，而是主要迁移到骨髓和过滤器官(如肝脏、肺和脾脏)[19]。到达局部肌肉的细胞少是静脉移植的不足。据此，人们想到了腓肠肌多点注射，但局部多点注射患者很痛苦，更重要的是细胞向四周迁移距离太短[28]，远远达不到人们预期的效果，而且不会对膈肌等部位产生效果。相对于静脉输注，动脉移植间充质干细胞治疗杜氏肌营养不良症是个不错的选择，研究表明：改用动脉移植干细胞治疗杜氏肌营养不良症，可以提高细胞定植的效率[29-30]。比如选择股动脉穿刺移植间充质干细胞，细胞通过毛细血管网直接进入腓肠肌等下肢肌肉，采用这样的方法可以确保移植的间充质干细胞最大限度地达到治疗部位。目前介入治疗技术发展迅速，借用介入治疗技术建立的通道，完全可以解决诸如膈肌等远端肌肉的干细胞移植治疗问题。因此，结合介入治疗技术可以改进提高干细胞移植治疗杜氏肌营养不良症的疗效。 2.4.4 间充质干细胞归巢的干预间充质干细胞移植到血液后，向受损组织位点靶向迁移的生物学特性即干细胞的归巢。间充质干细胞归巢机制尚不十分清楚，但目前认为间充质干细胞的归巢受SDF-1/CXCR4轴介导，与趋化因子和趋化因子受体等多种因素有关。基质衍生因子1(stromal cell derived factor-1，SDF-1)又名CXCL12，在损伤组织或炎性组织广泛表达[31]，目前发现其惟一受体是CXCR4(CXC chemokine receptor4)，CXCR4表达于间充质干细胞的细胞膜与细胞质[32]。带有CXCR4的间充质干细胞受SDF-1等信号分子引导被招募到受损组织位点，其迁移具有SDF-1浓度依赖性，这个介导调控系统即SDF-1/CXCR4轴被证实不仅在机体各个系统的发育中发挥重要作用，而且在干细胞动员和归巢过程中发挥着至关重要的作用。研究表明：由尾静脉移植脂肪来源的间充质干细胞后就能在心肌梗死模型大鼠心脏检测到植入间充质干细胞的存在[33]；采用基因转染方法使间充质干细胞高表达CXCR4基因，再将其移植给心肌梗死模型大鼠，就可发现到达心脏的间充质干细胞数量明显增加，对心脏损伤部位的修复明显增强，可见SDF-1/CXCR4轴对间充质干细胞归巢的调控是通过SDF-1或者CXCR4两个因子发挥作用的。研究显示：趋化因子和趋化因子受体组合不止SDF-1和CXCR4[34]，间充质干细胞除了表达CXCR4之外，还表达CCR1、CCR4、CCR7、CXCR5和CCR10等其他趋化因子受体，这些受体均具有趋化间充质干细胞迁移的功能。此外，有些因子还可通过影响SDF-1/CXCR4等主要调控因子的表达而间接发挥对间充质干细胞归巢的调控作用，比如血小板衍生因子、碱性成纤维细胞生长因子、肝细胞生长因子、表皮生长因子、血管内皮生长因子、转化生长因子β1等生长因子及其受体[35-37]。还有些因子可以通过影响间充质干细胞对毛细血管的黏附作用而影响其迁移，比如肿瘤坏死因子α和血管细胞黏附分子1[38]。目前已知这些因子与间充质干细胞归巢有关，但它们对间充质干细胞归巢的确切调控结果尚无统一定论甚至相互矛盾。研究者认为SDF-1/CXCR4轴是一个由多种因子共同组成的调控网络的重要组成部分，包括正向调控机制和负向调控机制，共同维持着内环境的平衡和稳定。事实上，细胞来源、细胞培养体系、细胞生长密集状态、细胞传代方式和传代次数等因素均会影响间充质干细胞的归巢[39-40]。显然，只要诱导发挥正向调控机制因子的表达就能促进间充质干细胞向损伤组织位点迁移，其结果就是增加到达损伤组织位点的细胞数量，这些细胞自然就可通过上述5种作用机制发挥治疗作用。因此，从干预间充质干细胞归巢的角度入手，提高间充质干细胞治疗杜氏肌营养不良症的效果，还有许多环节可以改进提高，至少包括：①筛选优化细胞培养方案，以促进间充质干细胞CXCR4等正向调控因子的表达。②选择间充质干细胞移植的时机，杜氏肌营养不良症患者肌细胞大量坏死早期比较有利于间充质干细胞的归巢，移植效果应该更好，而晚期假性肥大时治疗效果应该较差。③静脉移植间充质干细胞时同时给予某些调控因子(比如胰岛素样生长因子)，可能会促进间充质干细胞向损伤组织位点迁移，其作用机制与SDF-1/CXCR4轴有关。 2.4.5 加大间充质干细胞输注剂量或次数适当加大间充质干细胞输注数量，就可通过多种机制发挥间充质干细胞治疗杜氏肌营养不良症的效果，主要包括：①使更多的间充质干细胞到达肌肉组织，增加由其分化而成的新生健康肌肉细胞数量。②更好地发挥间充质干细胞的旁分泌功能，更多的营养因子促进内源性细胞的分裂增殖。③更多的间充质干细胞到达肌肉组织再生血管数量增加，血液循环更为充分，为肌细胞修复提供更多营养。④间充质干细胞分泌更多抗炎因子，减轻损伤肌组织的炎症反应。⑤有更多的细胞融合发生，生成更多的成熟肌细胞。"

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How to improve mesenchymal stem cells theropy for Duchenne muscular dystrophy?

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