Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (45): 7353-7357.doi: 10.3969/j.issn.2095-4344.2014.45.025
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Meng Xin-min1, Sun Xiao-lei1, Ma Jian-xiong1, Ma Xin-long2
Online:
2014-11-05
Published:
2014-11-05
Contact:
Ma Xin-long, Tianjin Hospital, Tianjin 300211, China
About author:
Meng Xin-min, Studying for master’s degree, Institute of Orthopedics, Tianjin Hospital, Tianjin 300211, China
Supported by:
the Science and Technology Fund of Tianjin Health Bureau, No. 2011KZ57; the Project of Tianjin Administration of Traditional Chinese Medicine, No. 13123
CLC Number:
Meng Xin-min, Sun Xiao-lei, Ma Jian-xiong, Ma Xin-long. Endothelial progenitor cells in fracture healing: problems about culture and transplantation[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(45): 7353-7357.
2.1 骨折愈合的血供 早在1763年,就有人提出血管对于骨的再生和修复有极为重要的作用[11]。骨折位点的血管生长在骨折后骨再生和愈合过程中扮演一个很重要的角色[12-13]。新鲜血液把氧气和营养物质运送给新陈代谢活跃的愈伤组织,并且作为炎症细胞、软骨细胞、骨祖细胞到达损伤处的通道[2,14]。血供不足是骨不愈合和延迟愈合的主要原因[15],前人研究表明伴随血管损伤的骨折患者骨折延迟愈合和不愈合的发生率高达46%[16]。 2.2 内皮祖细胞 2.2.1 内皮祖细胞的起源及鉴定 在胚胎发育早期,血液血管系统的形成是胚胎进一步发育的前提。胚胎时期血管的形成有两种相延续的方式:①血管发生(vasculogenesis),即由中胚层衍生的血管母细胞迁移、聚集、分化在原位形成大小相同的原始毛细血管网[17]。②血管新生(angiogenesis),即在原先存在的血管基础上血管内皮细胞增殖、迁移并重塑形成新的成熟血管[18]。最新的研究发现这种过程也可以发生在成熟生物体内。 1997年,Asahara等[7]首次证明出生后循环外周血中存在能分化为血管内皮细胞的前体细胞,作者把这些细胞称为内皮祖细胞。在后来的文献中有大量关于这类细胞起源和表面标记的描述[19],现普遍认为,内皮祖细胞与造血干细胞共同起源于胚胎期胚外中胚层的血岛,两者来源于同一前体细胞,即血液血管母细胞。内皮祖细胞可以被定义为一类骨髓来源的拥有分化成内皮细胞潜力的能够促进新血管形成的一类细胞,可以从骨髓中动员向外周血并且种植到靶器官如肝脏、脾脏、心脏、肌肉以及脂肪组织[20]。 Yoo等[4]研究发现,人牙髓细胞在体外可以诱导为CD34+的细胞,并且具有血管化能力,他们使用小鼠后肢缺血模型和心肌梗死模型进行了验证,发现由人牙髓细胞诱导分化来的内皮祖细胞很好地整合进新生血管中,并且通过直接或间接旁分泌作用诱导新生血管的形成。 早期的研究发现,内皮祖细胞表面表达造血干细胞标志物CD34与内皮细胞标志性蛋白血管内皮生长因子受体2(VEGFR2,即KDR)[21]。由于CD34在造血干细胞表面和成熟的内皮细胞上都有不同程度的表达,因此对于内皮祖细胞而言CD34并不具有特异性[22]。Gehling 等[23]发现,纯化的CD133阳性祖细胞可以在体外分化为成熟的内皮细胞,而进一步研究发现,CD133是早期造血干细胞上一种高度保守的抗原标志物,在成熟的内皮细胞上并不表达,可以此与内皮细胞相鉴别。因此,内皮祖细胞既可以表达早期造血干细胞的标志CD34与CD133,同时又可以表达内皮细胞上的表面标志物VEGFR2。 但是对于内皮祖细胞表面标记物的特异性鉴定仍然存在很大的争议[24]。现在比较公认的是内皮祖细胞能够来源于骨髓[21],并且CD133/VEGFR2阳性的细胞可以被看做具有内皮组细胞功能的细胞群。今后的研究重点应该明确内皮祖细胞的鉴定,使之标准化、规范化,以便在临床、科研中有一个共同的研究标准[25-26]。 2.2.2 内皮祖细胞的动员和趋化作用 骨髓中干细胞的动员决定于局部微环境的变化,包括成纤维细胞、成骨细胞和内皮细胞[27]。文献报道缺血可以上调血管内皮生长因子和基质细胞衍生因子1的表达[28],并且会通过基质金属蛋白酶9依赖的机制反过来抑制内皮祖细胞和基质细胞的相互作用,从而使内皮祖细胞从骨髓动员向外周血[29]。 2.2.3 内皮祖细胞与一氧化氮、血管内皮生长因子、促红细胞生成素的作用 从20世纪60年代开始,有大量研究证明细胞因子在血管生成和骨愈合中扮演着很重要的角色,例如一氧化氮、血管内皮生长因子和促红细胞生成素等[30-32]。 一氧化氮,即内皮来源血管舒张因子,在血管内皮平滑肌的舒张作用中起调控作用,从而引起平滑肌舒张,血流量上升[33]。内皮型一氧化氮合酶具有合成一氧化氮来调节血管张力、抑制平滑肌收缩和血小板聚集的作用。研究表明,基质金属蛋白酶9可以被一氧化氮激活,并且参与内皮祖细胞从骨髓向外周血的动员[34]。因此,内皮型一氧化氮合酶缺陷可能不利于内皮祖细胞从骨髓动员,从而影响缺血环境下的血管再生。 血管内皮生长因子是一种在新血管形成中起重要作用的信号蛋白,能够穿透血管壁,并且可能具有促进内皮细胞增殖、分化、成熟并抑制内皮细胞凋亡的作用。此外,它也可能具有其他的功能例如诱导血管平滑肌细胞迁移、促进基质金属蛋白酶的合成和分泌、诱导炎症因子的趋化作用,从而促进新生毛细血管的形成。研究表明,血管内皮生长因子在促进内皮祖细胞的分化和成熟中有重要的作用[35]。 促红细胞生成素:是一种调控红细胞生成的糖蛋白激素,研究表明,促红细胞生成素可以促进内皮细胞有丝分裂,增强缺血组织的成血管作用[36]。此外,促红细胞生成素和血管内皮生长因子在血管形成中同等重要,在对内皮细胞成血管潜力的作用中表现相似。 2.2.4 内皮祖细胞与血管再生 内皮祖细胞在血管形成中起着重要的作用,并且具有增殖、分化成内皮细胞的能力,这使得它们成为一种理想的选择来治疗血管相关性疾病,现在的技术已经可以通过体外扩增内皮祖细胞并移植到缺血部位来实现。例如,有研究表明,使用外周血来源的内皮祖细胞、骨髓单个核细胞或者纯化的CD34(+)细胞进行灌注治疗,可以增强血管再生能力、修复心肌功能[8]。 2.3 内皮祖细胞与骨折愈合 血管新生需要一系列复杂的生物过程。Ma等[37]通过检测不同时间点24例长骨骨折患者外周血中内皮祖细胞的含量发现,创伤性骨折患者外周血中内皮祖细胞的含量明显高于同年龄同性别的健康人群,并且在伤后3 d达高峰;不同性别与不同创伤严重性之间差异无显著性意义;但是在年轻患者中早期内皮祖细胞的含量高于老年患者。说明创伤可能会诱导内皮祖细胞动员向外周血,而外周血内皮祖细胞的升高可能会促进新生血管形成并促进骨折愈合。 Li等[38]将接种有内皮祖细胞的明胶海绵支架移植入F344大鼠部分骨缺损模型体内,第10周内皮祖细胞治疗组所有7只大鼠骨折愈合良好,而对照组出现了骨折不愈合的缺陷。Micro-CT分析证明了这一点,生化检测发现内皮祖细胞治疗组的骨抗扭强度和刚度都明显高于对照组。这个实验说明内皮祖细胞治疗可以明显强化骨折愈合,增强骨再生。 也有人研究内皮祖细胞在体内的分布问题。Lee等[39]研究了牵拉骨形成和骨折愈合中内皮祖细胞的比例变化,研究动员的内皮祖细胞是否能够迁移到骨再生位点参与新生血管形成。作者在研究中使用了鼠胫骨骨折和牵拉骨形成模型,相对于非手术对照组,骨折组外周血内皮祖细胞水平在骨折后3 d增加了将近7倍。在牵拉骨形成模型中,内皮祖细胞比例在截骨术后3 d明显上升,随后逐渐下降到基础水平。有趣的是,相对于截骨术后不进行牵拉固定的组别来说,牵拉骨形成组内皮祖细胞数量在牵拉和固定期明显增多。作者发现牵拉期近截骨间隙的相对血流会增加,并一直持续到牵拉期结束,而且在固定期达峰值。作为这个研究的一部分,体外扩增并标记的内皮祖细胞经静脉被移植入牵拉骨形成动物模型中来研究这些细胞的作用。研究发现移植的细胞首先在脾脏富集,这种现象产生的原因可能与脾脏的免疫功能有关。Lee等指出,尽管在骨再生位点只有少量移植细胞,他们仍观察到移植细胞数与牵拉间隙细胞数有明显的数量依赖关系,同时在对侧非手术胫骨中并没有检测到标记的内皮祖细胞。 有没有什么方法可以促进内皮祖细胞在骨再生位点的归巢呢?Sun等[40]使用大鼠后肢缺血模型以及股骨骨折模型研究发现,岩藻糖基化可以促进路易斯蛋白(SLex)在内皮祖细胞的表达,从而增加缺血位点内皮祖细胞的归巢,增强缺血部位血流量和血管化水平。路易斯蛋白是选择蛋白(selectin)的一种,在介导的细胞相互间作用中相当重要,可以促进细胞的迁移和趋化[41]。 近3年来,关于内皮祖细胞与骨折愈合的研究逐渐由动物转向人,逐渐向其促血管、促进骨形成的机制进行深入研究,甚至出现了临床应用细胞进行治疗的案例。Kuroda等[42]报道了第1例接受自体来源的、通过粒细胞集落刺激因子动员的CD34+细胞来治疗胫骨骨折不愈合的病例,3D-CT检查发现术后3个月患者骨折愈合,此时患者已经可以完全负重并且没有任何不适。Fukui等[43]的研究发现CD34+细胞比人外周血单个核细胞具有更优良的成血管能力。 2.4 内皮祖细胞与间充质干细胞相互作用 随着内皮祖细胞生物学和其作用机制的研究越来越深入,有一些证据表明这些细胞具有促血管化和促成骨两方面的作用,分别影响内皮细胞和成骨细胞的分化过程。此外,内皮祖细胞还可以通过旁分泌的作用释放生长因子和细胞因子来促进血管化和成骨作用。 Li等[44]将种植有内皮祖细胞的明胶海绵支架植入骨缺损大鼠体内,结果发现,第10周内皮祖细胞移植组大鼠骨折完全愈合,而对照组出现骨不愈合情况,骨形态发生蛋白2 mRNA表达量在第1,2,3周都明显高于对照组,并且在第1周达峰,随后逐渐下降,第10周已经与对照组没有差异。这个结果的出现,可能会对进一步理解内皮祖细胞促进骨愈合的机制有所帮助。Kaigler等[45]发现将内皮祖细胞与间充质干细胞在体外进行接触式共培养,可以显著增强间充质干细胞的成骨分化能力,而调控机制可能是由于内皮祖细胞分泌产生骨形态发生蛋白2促进间充质干细胞向成骨方向分化。Raida等[46]也通过实验进一步证实,骨形态发生蛋白2是内皮祖细胞与间充质干细胞两者之间进行Cross-talk 的重要“信使”。 最近还有研究表明外周血来源的内皮祖细胞在间充质干细胞作用下可以促进成骨分化,间充质干细胞可以促进内皮祖细胞增殖并在内皮祖细胞网中起固定作用[47]。Aguirre等[48]研究了体外共培养体系中骨髓来源内皮祖细胞和间充质干细胞之间的物理、生化作用。数据表明,骨髓来源内皮祖细胞和间充质干细胞之间通过旁分泌作用和直接的细胞接触机制进行相互作用,并共同作用于血管化反应。作者指出这两种细胞之间的相互作用可能会增强骨折点的骨愈合。 尽管内皮祖细胞与间充质干细胞之间的作用机制还需要进一步阐明,但毫无疑问这些研究的出现为联合使用内皮祖细胞与间充质干细胞促进骨愈合提供了依据,也为今后组织工程应用提供了一个新的方向。"
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