Research Progress on Osteogenic Differentiation of Apical Papilla Stem Cells
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摘要: 根尖牙乳头干细胞(stem cells from apical papilla,SCAP)具有很强的多系分化潜能,其中成骨分化可以应用于骨组织再生,为口腔颌骨缺损治疗提供新思路。成骨分化是个复杂的网络调控过程,诸如各种细胞因子、表观遗传物质、各种信号分子和信号通路等内源性物质均可产生不同程度的影响。这些因素相互作用可以促进SCAP的增殖、迁移和成骨分化,但其在SCAP成骨分化的不同进程中的具体机制和内在联系各不相同。对近年来有关促进SCAP成骨分化的各种因素及其可能的调控机制研究文献进行综述,以期为其进一步的应用研究提供新信息。Abstract: Stem cells from apical papilla (SCAP) have a strong multi-line differentiation potential, in which osteogenic differentiation can be applied to bone tissue regeneration, providing a new idea for the treatment of oral jaw defects. Osteogenic differentiation is a complex network regulation process, and endogenous substances such as various cytokines, epigenetic material, various signaling molecules and signaling pathways can have different degrees of influence. The interaction of these factors can promote the proliferation, migration and osteogenic differentiation of SCAP, but the specific mechanisms and internal links in different processes of osteogenic differentiation of SCAP are different. In this paper, the factors that promote osteogenic differentiation of SCAP and their possible regulatory mechanisms were reviewed to provide new information for further application research.
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临床中存在大量因为根尖疾病、牙周疾病以及其他骨性疾病导致颌骨缺损的患者,严重影响患者生理和心理健康。目前常规的治疗方法并不能恢复原本组织的生理功能,因此骨再生一直是口腔再生医学研究的热点。细胞是组织工程的关键要素,牙源性的间充质干细胞(mesenchymal stem cells,MSC)是一种稳定可靠的组织再生资源,目前已经被分离和鉴定的人类牙源性干细胞很多种,包括牙髓干细胞(dental pulp stem cells,DPSC)、根尖乳头干细胞(stem cells from apical papilla,SCAP)、脱落乳牙干细胞(stem cells from human exfoliated decidulous teeth,SHED)和牙周膜干细胞(periodontal ligament stem cells,PDLSC) [1]。其中SCAP是最早由Sonoyama等[2]从根尖孔未闭合的牙齿中分离出来的一组具有干细胞特性的细胞群,大量证据表明SCAP能够分化成各种谱系的细胞,如成骨细胞、牙源性细胞、神经源性细胞、脂肪细胞和软骨细胞等[3],研究表明SCAP比PDLSC和DPSC表现出明显更高的增殖率和矿化潜力[4−5],被认为是成骨分化优良的种子干细胞,近年来备受关注。本文主要就对SCAP成骨分化影响的相关因素研究进展进行综述,以期为临床提供有价值的信息。
1. 细胞因子与SCAP成骨分化
1.1 TGF-β
转化生长因子-β1(transforming growth factor-β1,TGF-β1)能促进SCAP生长和胶原合成,浓度为0.1~1 ng/mL时上调碱性磷酸酶(alkaline phosphatase,ALP)活性,大于5 ng/mL时则下调。同时刺激ERK1/2和Smad2磷酸化,激活ALK5/Smad2和MEK/ERK信号通路,影响SCAP的增殖、胶原合成和分化。U0126(MEK/ERK抑制剂)和SB431542(ALK5/Smad2抑制剂)可有效抑制TGF-β1对SCAP的诱导[6]。TGF-β2主要促进SCAP的成牙本质分化,减弱SCAP成骨分化,但TGF-β2被发现在SCAP成骨分化过程中表达显著上调,在早期抑制骨涎蛋白的表达,敲除后增加了骨钙素(osteocalcin,OCN)和RUNX2的表达,而敲除TGF-β1具有相反的效果,说明TGF-β1和TGF-β2可能保持一种动态平衡影响SCAP成骨分化[7−8]。
1.2 骨形态发生蛋白
骨形态发生蛋白(bone morphogenetic protein,BMP)是调节成骨分化最关键的因子之一。BMP2上调ALP和OCN表达,促进SCAP成骨矿化[9]。Foxc2是BMP2调控的转录因子,第 4天和第8天过表达Foxc2显著促进了SCAP的增殖,8 d后则显著抑制其增殖。另外,Foxc2和BMP2可协同促进并上调SCAP成骨相关基因和蛋白表达[10]。BMP2和血管内皮生长因子共转染SCAP 后抑制增殖,但ALP、OCN的表达水平和矿化结节的数量显著升高[11]。另外,转录因子早期生长反应基因1过表达上调DLX3和BMP2表达增强SCAP成骨[12]。BMP9能刺激SCAP在体内分化为骨和软骨细胞,显著上调RUNX2、SOX9、PPARγ2并增强ALP活性和SCAP的基质矿化[13]。TNF-α作为一种炎症因子可抑制BMP9对SCAP的诱导,但高水平BMP9可部分逆转其抑制作用[14]。Wnt3A和BMP9可协同增强ALP活性,体内实验证明 BMP9和Wnt3A比BMP9诱导的SCAP表现出更成熟和高度矿化的骨小梁 [15]。GREM1是BMP的拮抗剂,在mRNA水平上下调BMP2、BMP6、BMP7从而促进SCAP成骨分化,抑制SCAP增殖和衰老 [16]。
1.3 其他细胞因子
胰岛素样生长因子(insulin like growth factor,IGF)主要包括IGF-1和IGF-2,是一类多功能细胞增殖调控因子。IGF-1促进SCAP增殖和成骨,ALP、RUNX2、OCN、OSX的蛋白表达显著上调,在体内实验中IGF-1更倾向促进SCAP分化为成骨细胞 [17]。MicroRNA let-7家族是MSC分化的关键调控因子, hsa-let-7b在SCAP成骨分化过程中表达明显下调[18]。IGF-1/IGF-1R/hsa-let-7c轴通过调控JNK和p38 MAPK信号通路来控制IGF-1对SCAP成骨的作用,低表达hsa-let-7c可显著促进SCAP矿化,JNK和p38 MAPK信号通路被激活;过表达则相反[19]。
细胞因子是分泌或膜呈现的分子,介导广泛的细胞功能,包括发育、分化、生长和生存。在调节细胞因子的作用方面,使用的策略非常广泛,这一领域正在迅速扩大,有很大潜力为一系列疾病创造改进的治疗方法。
2. 信号分子与SCAP成骨分化
信号分子是指生物体内的某些化学分子,其主要是用来在细胞间和细胞内传递信息,如激素和神经递质等,它们的唯一功能是同细胞受体结合,传递细胞信息。
激素是由细胞合成和释放,是人体信息传递的“第一信使”。17-雌二醇是一类雌激素物质,可激活MAPK信号通路,上调p-P38和p-JNK蛋白水平[20]。雌激素受体作为一种常见的调节细胞增殖和分化的细胞核受体,与激素结合形成复合物,过表达激活ERK和JNK MAPK通路促进SCAP成骨[21]。10-8 mol/L 的甲状旁腺激素是诱导SCAP成骨分化的最佳浓度,并通过JNK和P38 MAPK通路调控[22]。
环磷酸腺苷(cyclic adenosine phosphate,cAMP)是生命信息传递的“第二信使”。将cAMP装载在SCAP中形成LBL-cAMP-SCAP复合体,不仅对细胞增殖和活力无显著影响,而且cAMP可持续释放上调成骨相关基因mRNA和蛋白水平,增强cAMP反应元件结合蛋白磷酸化水平促进SCAP成骨[23−24]。在cAMP激活剂和 TGF-β1抑制剂共同作用下,cAMP信号通路通过抑制Smad3和ERK磷酸化,干扰TGF-β1信号通路,从而促进SCAP成骨[25]。基质衍生因子-1α 是一种趋化因子信号分子,与跨膜受体CXC趋化因子受体-4结合可促进SCAP迁移,但将其阻断后激活Smad和ERK通路可抑制BMP2对SCAP的诱导[26]。
细胞通过识别各种信号并与受体结合,产生特异性的胞内信号分子,进一步产生有调控的级联反应,改变胞内某些代谢过程,适应细胞代谢、增殖、生长、分化、凋亡等复杂生命活动的需要。尽管这可能是研究中最为困难的部分之一,但在研究的深度将产生深远的影响。
3. 表观遗传与SCAP成骨分化
表观遗传由多种机制调控,对机体生理活动具有重要意义,其中非编码RNA调控和组蛋白修饰在SCAP成骨分化中研究较多。
3.1 非编码RNA调控对SCAPs成骨分化的影响
非编码RNA按照大小可分为短链非编码RNA和长链非编码RNA。microRNAs是一类短链、非编码的内源性RNA,决定着组织和细胞的功能特异性。
miR-497-5p通过Smad信号通路靶向作用Smad蛋白E3泛素连接酶2从而负向调控SCAP成骨分化[27]。miR-141-3p同样负向调控,沉默后促进SCAP成骨分化和增殖并延缓衰老[28]。circRNAs已知在各种细胞分化过程中发挥关键的调节功能,circ-ZNF236是一个高度稳定的共价闭环结构,可通过上调LGR4的表达激活自噬从而正向调控SCAPs成骨分化过程[29]。
长链非编码RNA(long noncoding RNA, lncRNA)在转录和转录后水平上发挥着转录调控、干细胞增殖和分化等功能。lncRNA-H19参与促进细胞生长、侵袭、迁移、上皮-间质转化、转移和凋亡。过表达H19促进SCAP成骨分化,另外,H19竞争性地与miR-141结合,阻止了SPAG9在microRNA介导下的降解,并显著提高p38和JNK的磷酸化水平[30]。
3.2 组蛋白修饰对SCAP成骨的影响
组蛋白修饰主要由组蛋白甲基转移酶和去甲基化酶控制,组蛋白去甲基化酶家族调控着MSC的分化。赖氨酸特异性组蛋白去甲基化酶1( lysine-specific histone demethylase 1,KDM1A)可能与2-氧戊二酸5-双加氧酶2结合形成蛋白复合物在骨分化的不同阶段发挥不同的作用,最终导致对SCAP骨分化的抑制,下调KDM1A反而促进[31]。KDM2A和KDM2B是进化保守且普遍表达的包含JmjC结构域的组蛋白去甲基化酶家族成员。KDM2A通过p15和p27的位点调节SCAP增殖,沉默KDM2A增加p15和p27位点的组蛋白H3赖氨酸4的三甲基化(trimethylation of histone H3 lysine 4,H3K4Me3),分化的SCAP的H3K4Me3表达量比未分化的SCAP增加了2倍[32−33]。SNRNP200作为KDM2A的共结合因子,缺失导致ALP、RUNX2、BSP表达明显降低。敲除SNRNP200通过阻断G2/M和S期进而抑制SCAP的增殖,并上调p21和p53,下调CDK1、CyclinB、CyclinE和CDK2,抑制骨分化潜能[34]。KDM3B促进SCAP表达RUNX2、OSX和OCN,Toll样受体和JAK-STAT信号通路可能参与其中[35]。
表观遗传机制在组织发育、维护和修复过程中介导了特殊细胞表型的获得。SCAP增殖和分化依赖于表观遗传DNA和组蛋白修饰,以及其他“标记”基因组的结构结合蛋白,探寻相关的表观遗传机制可能是一种新的治疗靶点。
4. HOX和DLX基因与SCAP成骨分化
近年来的研究发现HOX基因作为高度保守的同型超级家族的子集,编码几种作用作为转录因子的序列特异性DNA结合蛋白,参与调控MSC骨分化和形成。HOXA5缺失上调SCAP中p16 INK4A和p18 INK4C表达并下调Cyclin A将细胞周期进展阻滞在S期,从而抑制成骨分化和细胞增殖[36]。HOXB7通过上调RUNX2,促进SCAP成骨分化,过表达可进一步增强[37]。HOXC8和HOXC10均负向调控SCAP,HOXC8通过直接结合KDM1A的启动子增强KDM1A的转录,二者也抑制了SCAP的迁移和趋化能力[38−39]。
DLX2和DLX5基因在牙源性MSC中高度表达,KDM4B可通过上调DLX2和DLX5促进成骨。BMP4诱导DLX2、DLX5和KDM4B上调,三者均通过正反馈机制相互调节[40]。另外,DLX5和HOXC8通过直接结合LncRNA启动子形成蛋白复合物负向调控LncRNA LINC01013,增强SCAP向软骨分化[41]。
新型转录抑制因子ZHX2属于锌指和HOX家族,广泛存在于各种组织细胞核内。过表达ZHX2可上调成骨相关基因表达并抑制SCAP的增殖,抑制ZHX2则效果相反[42]。过表达转录因子Nuclear factor I-C促进SCAP增殖和矿化结节形成,上调ALP和OCN蛋白水平;敲除则作用相反[43]。
HOX和DLX基因是脊椎动物颅面结构调控的关键转录因子,如果缺失可能导致严重后果,若能探寻其在SCAP成骨分化过程中的机制,则可以对SCAP进行改造修饰用以疾病的治疗。
5. 信号通路与SCAP成骨分化
经典Wnt/ catenin信号通路已被证明促进SCAP的增殖和成骨分化。WIF1和分泌卷曲相关蛋白2(secreted frizzled related protein 2,SRFP2)是一种Wnt抑制剂,过表达WIF1可增强体外ALP活性和矿化,增强SCAP中OSX的表达[44]。SRFP2通过增强磷酸化和降低β-catenin的表达来抑制典型Wnt信号通路进而抑制NF-kB信号通路靶基因,并且Wnt信号通路的靶基因AXIN2和MMP7也被SFRP2下调。SFRP2可以与局部存在的Wnt配体结合,改变细胞内Wnt信号的平衡,从而拮抗SCAP中典型的Wnt通路[45]。炎症和缺氧条件下,过表达SFRP2可增强骨分化能力并促进KDM2A的表达,最终促进SCAP分泌更多功能性细胞因子,提高迁移、趋化和成骨能力[46]。G蛋白偶联受体4基因下调后阻断Wnt/ catenin信号通路抑制SCAP的增殖、迁移和成骨分化,沉默后可降低RUNX2、OSX和OCN的表达[47]。2.5 μg/mL浓度的抗菌肽LL-37也可通过激活AKT/Wnt/β-catenin信号通路促进SCAP的迁移和成骨分化[48]。
Shh信号通路是调节细胞分化和成骨的主要信号通路。Shh信号通路的关键下游转录因子和标记物GLI1表达上调,SCAP成骨受到抑制,而BMP信号可下调GLI1和SMO,逆转SCAP成骨分化[49]。ERK和p38 MAPK通路在SCAP成骨分化中研究颇多。脂多糖(lipolyaccharide,LPS)是一种内毒素,0.1 μg/mL LPS促进SCAP增殖,ALP、RUNX2和BSP 表达升高。5 μg/ mL LPS抑制SCAP成骨分化,降低RUNX2和ALP表达。LPS增强p-ERK和p-p38的表达,抑制ERK和p38 MAPK通路可显著抑制细胞分化[50]。
信号通路在基础研究中的作用不言而喻,目前已经研究发现Wnt/ catenin等经典信号通路在SCAP成骨分化中的重要性,但还有一些潜在的信号通路尚未被研究,通过调节信号通路耦合其他信号分子可能不失为一种有价值的方向。
6. 小结
综上所述,能够调控SCAP成骨分化的物质和机制不止于此,诸如云南白药和黄连素等中药,氢氧化钙、MTA和iRoot BP等口腔材料以及光源性物质和机械应力等均能对SCAP成骨分化产生积极的影响。目前,大多数研究都是单一因素介导单一信号通路机制,并未深入探索更复杂调控网络,而且其对SCAP成骨的具体影响并未做定量比较,难以判断其效果强弱。未来研究可以具体到单个因素,分析其上下游基因和蛋白的变化,研究它们之间的协同关系,明确其调控轴。这将有助于临床工作者确定促进SCAP成骨分化的最佳的单个或多个因素,为SCAP在口腔再生医学中的应用提供进一步的指导。
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