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根尖牙乳头干细胞成骨分化的研究进展

钱石兵 史会萍 李艳秋 杨镕羽 段开文

钱石兵, 史会萍, 李艳秋, 杨镕羽, 段开文. 根尖牙乳头干细胞成骨分化的研究进展[J]. 昆明医科大学学报, 2024, 45(9): 168-173. doi: 10.12259/j.issn.2095-610X.S20240926
引用本文: 钱石兵, 史会萍, 李艳秋, 杨镕羽, 段开文. 根尖牙乳头干细胞成骨分化的研究进展[J]. 昆明医科大学学报, 2024, 45(9): 168-173. doi: 10.12259/j.issn.2095-610X.S20240926
Shibing QIAN, Huiping SHI, Yanqiu LI, Rongyu YANG, Kaiwen DUAN. Research Progress on Osteogenic Differentiation of Apical Papilla Stem Cells[J]. Journal of Kunming Medical University, 2024, 45(9): 168-173. doi: 10.12259/j.issn.2095-610X.S20240926
Citation: Shibing QIAN, Huiping SHI, Yanqiu LI, Rongyu YANG, Kaiwen DUAN. Research Progress on Osteogenic Differentiation of Apical Papilla Stem Cells[J]. Journal of Kunming Medical University, 2024, 45(9): 168-173. doi: 10.12259/j.issn.2095-610X.S20240926

根尖牙乳头干细胞成骨分化的研究进展

doi: 10.12259/j.issn.2095-610X.S20240926
基金项目: 国家自然科学基金资助项目(81160135);云南省生物医药重大科技专项基金(202102AA100007);云南省教育厅科学研究基金教师类项目(2024J1609)
详细信息
    作者简介:

    钱石兵(1996~),男,云南曲靖人,医学硕士,助教,主要从事牙周病和口腔黏膜疾病的防治工作

    通讯作者:

    段开文,E-mail:kwduan@aliyun.com

  • 中图分类号: R78

Research Progress on Osteogenic Differentiation of Apical Papilla Stem Cells

  • 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。
  • 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[45],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。

    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[78]

    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]

    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。

    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[2324]。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。

    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。

    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]

    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[3233]。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。

    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[3839]

    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。

    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。

    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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  • 收稿日期:  2023-12-05
  • 网络出版日期:  2024-09-03
  • 刊出日期:  2024-09-25

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