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Article(id=1246459853401641608, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, articleNumber=null, orderNo=null, doi=10.12307/2025.560, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1718726400000, receivedDateStr=2024-06-19, revisedDate=1731254400000, revisedDateStr=2024-11-11, acceptedDate=1727107200000, acceptedDateStr=2024-09-24, onlineDate=1775108787155, onlineDateStr=2026-04-02, pubDate=1766851200000, pubDateStr=2025-12-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1775108787155, onlineIssueDateStr=2026-04-02, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1775108787155, creator=13701087609, updateTime=1775108787155, updator=13701087609, issue=Issue{id=1246459843930903036, tenantId=1146029695717560320, journalId=1246415837536497731, year='2025', volume='29', issue='36', pageStart='7701', pageEnd='7920', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=null, createTime=1775108784853, creator=13701087609, updateTime=1775108852483, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1246460127511991018, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1246460127511991019, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=7769, endPage=7775, ext={EN=ArticleExt(id=1246459854135644834, articleId=1246459853401641608, tenantId=1146029695717560320, journalId=1246415837536497731, language=EN, title=Effect of miR-26b on neural and vascular differentiation in stem cells from human exfoliated deciduous teeth, columnId=1246459844752986623, journalTitle=Chinese Journal of Tissue Engineering Research, columnName=Research, runingTitle=null, highlight=null, articleAbstract=
BACKGROUND:

Stem cells from human exfoliated deciduous teeth are widely used in the field of tissue repair and regeneration, but the tissue regeneration effect has limitations in practical applications. Using miRNA to intervene in the directional differentiation of stem cells from human exfoliated deciduous teeth is an important development direction for tissue repair and regeneration in the future.

OBJECTIVE:

To investigate the effect of miR-26b on the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth.

METHODS:

Dental pulp stem cells were isolated and extracted from human exfoliated deciduous teeth, and induced to differentiate into nerves and blood vessels. The expressions of neurogenic markers Nestin, NSE, βIII-Tubulin, and angiogenic markers CD31, VEGFR2, ANG-1 and miR-26b were detected. Dental pulp stem cells were divided into blank control group, miR-26 overexpression group, and negative control group. RT-qPCR, cell immunofluorescence staining, and western blot assay were used to detect the expression changes of related markers of neurogenic and angiogenic induction of stem cells from human exfoliated deciduous teeth in each group.

RESULTS AND CONCLUSION:

(1) Stem cells from human exfoliated deciduous teeth had multi-directional differentiation potential and could differentiate into osteogenesis, adipogenesis, neurogenesis, and vasculogenesis. (2) The expression level of miR-26b increased during the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth. (3) Compared with the blank control group and negative control group, the mRNA expression of neuroblast-related genes βIII-Tubulin, Nestin, NSE and angiogenesis-related genes CD31, VEGFR2, and ANG-1 in stem cells from human exfoliated deciduous teeth in the miR-26b overexpression group was significantly increased (P < 0.01), βIII-Tubulin, Nestin, CD31, and VEGFR2 protein expression was significantly increased (P < 0.01). The above results show that overexpression of miR-26b can promote the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth.

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Yuan Yuanyuan, MS, Associate chief physician, School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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背景：

人脱落乳牙牙髓干细胞广泛应用于组织修复再生领域，但组织再生效果在实际应用中存在局限性。利用miRNA干预人脱落乳牙牙髓干细胞的定向分化是未来组织修复再生的重要发展方向。

目的：

探讨miR-26b对乳牙牙髓干细胞成神经及成血管分化能力的影响。

方法：

从人脱落乳牙中分离提取乳牙牙髓干细胞，并将其向神经及血管方向诱导分化，分别检测成神经标志物Nestin、NSE、βⅢ- Tubulin和成血管标志物CD31、VEGFR2、ANG-1及miR-26b的表达。然后将乳牙牙髓干细胞分为空白对照组、miR-26过表达组和阴性对照组，RT-qPCR、细胞免疫荧光染色及Western blot检测各组乳牙牙髓干细胞成神经及成血管诱导后相关标志物的表达变化。

结果与结论：

①乳牙牙髓干细胞具有多向分化潜能，能向成骨、成脂、成神经及成血管方向分化；②在乳牙牙髓干细胞成神经及成血管分化过程中miR-26b表达水平升高；③相较于空白对照组和阴性对照组，miR-26b过表达组乳牙牙髓干细胞成神经相关基因βⅢ-Tubulin、Nestin、NSE及成血管相关基因CD31、VEGFR2、ANG-1的mRNA表达显著升高（P < 0.01），βⅢ-Tubulin、Nestin及CD31、VEGFR2蛋白表达显著升高（P < 0.01）。以上结果表明，miR-26b过表达能促进人脱落乳牙牙髓干细胞成神经和成血管诱导分化。

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袁媛园，硕士，副主任医师，贵州医科大学口腔医学院，贵州省贵阳市　550004
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作者贡献：

周绍兰负责实验实施以及论文撰写，徐文负责细胞培养，潘露负责相关指标检测，瞿姝熳负责数据分析与处理，袁媛园负责实验设计、统计学分析以及论文修改。

Zhou Shaolan, MS, Physician, School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China

周绍兰，女，1996年生，贵州省贵阳市人，汉族，2023年贵州医科大学毕业，硕士，医师，主要从事牙体牙髓病学相关工作，以及牙髓干细胞方向研究工作。

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Zhou Shaolan, MS, Physician, School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China

周绍兰，女，1996年生，贵州省贵阳市人，汉族，2023年贵州医科大学毕业，硕士，医师，主要从事牙体牙髓病学相关工作，以及牙髓干细胞方向研究工作。

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Zhou Shaolan, MS, Physician, School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China

周绍兰，女，1996年生，贵州省贵阳市人，汉族，2023年贵州医科大学毕业，硕士，医师，主要从事牙体牙髓病学相关工作，以及牙髓干细胞方向研究工作。

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RNA. 2022; 29(1): 69-81., articleTitle=lncRNA Malat1 and miR-26 cooperate in the regulation of neuronal progenitor cell proliferation and differentiation, refAbstract=null), Reference(id=1246459879393743441, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2012, volume=26, issue=1, pageStart=25, pageEnd=30, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=DILL H, LINDER B, FEHR A, journalName=Genes Dev, refType=null, unstructuredReference=DILL H, LINDER B, FEHR A, et al. Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes Dev. 2012; 26(1): 25-30., articleTitle=Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2, refAbstract=null), Reference(id=1246459879544738389, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2021, volume=25, issue=23, pageStart=10892, pageEnd=10901, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=WANG JH, HE DE, journalName=J Cell Mol Med, refType=null, unstructuredReference=WANG JH, HE DE. Simvastatin treatment promotes proliferation of human dental pulp stem cells via modulating PI3K/AKT/miR-9/KLF5 signalling pathway. J Cell Mol Med. 2021; 25(23): 10892-10901., articleTitle=Simvastatin treatment promotes proliferation of human dental pulp stem cells via modulating PI3K/AKT/miR-9/KLF5 signalling pathway, refAbstract=null), Reference(id=1246459879699927645, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2019, volume=52, issue=12, pageStart=1691, pageEnd=1703, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=SUN X, MENG L, QIAO W, journalName=Int Endod J, refType=null, unstructuredReference=SUN X, MENG L, QIAO W, et al. Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways. Int Endod J. 2019; 52(12): 1691-1703., articleTitle=Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways, refAbstract=null), Reference(id=1246459879796396642, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2019, volume=68, issue=Suppl 2, pageStart=S131, pageEnd=S138, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=SAMAKOVA A, GAZOVA A, SABOVA N, journalName=Physiol Res, refType=null, unstructuredReference=SAMAKOVA A, GAZOVA A, SABOVA N, et al. The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019; 68(Suppl 2): S131-S138., articleTitle=The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia, refAbstract=null), Reference(id=1246459879888671333, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2021, volume=265, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=HE J, ZHANG N, ZHU Y, journalName=Biomaterials, refType=null, unstructuredReference=HE J, ZHANG N, ZHU Y, et al. MSC spheroids-loaded collagen hydrogels simultaneously promote neuronal differentiation and suppress inflammatory reaction through PI3K-Akt signaling pathway. Biomaterials. 2021; 265:120448., articleTitle=MSC spheroids-loaded collagen hydrogels simultaneously promote neuronal differentiation and suppress inflammatory reaction through PI3K-Akt signaling pathway, refAbstract=null), Reference(id=1246459880006111851, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2016, volume=117, issue=6, pageStart=1370, pageEnd=1383, url=null, language=null, rfNumber=[35], rfOrder=34, authorNames=ZHU A, KANG N, HE L, journalName=J Cell Biochem, refType=null, unstructuredReference=ZHU A, KANG N, HE L, et al. MiR-221 and miR-26b Regulate Chemotactic Migration of MSCs Toward HGF Through Activation of Akt and FAK. J Cell Biochem. 2016; 117(6): 1370-1383., articleTitle=MiR-221 and miR-26b Regulate Chemotactic Migration of MSCs Toward HGF Through Activation of Akt and FAK, refAbstract=null), Reference(id=1246459880089997932, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2021, volume=14, issue=9, pageStart=1350, pageEnd=1358, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=SHI E, YE XN, XIE LY, journalName=Int J Ophthalmol, refType=null, unstructuredReference=SHI E, YE XN, XIE LY. miRNA-26b suppresses the TGF-β2-induced progression of HLE-B3 cells via the PI3K/Akt pathway. Int J Ophthalmol. 2021; 14(9): 1350-1358., articleTitle=miRNA-26b suppresses the TGF-β2-induced progression of HLE-B3 cells via the PI3K/Akt pathway, refAbstract=null), Reference(id=1246459880186466930, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2021, volume=21, issue=4, pageStart=568, pageEnd=576, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=ZHOU Y, QIAO H, LIU L, journalName=J Musculoskelet Neuronal Interact, refType=null, unstructuredReference=ZHOU Y, QIAO H, LIU L, et al. miR-21 regulates osteogenic and adipogenic differentiation of BMSCs by targeting PTEN. J Musculoskelet Neuronal Interact. 2021; 21(4): 568-576., articleTitle=miR-21 regulates osteogenic and adipogenic differentiation of BMSCs by targeting PTEN, refAbstract=null), Reference(id=1246459880287130226, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2017, volume=36, issue=8, pageStart=672, pageEnd=681, url=null, language=null, rfNumber=[38], rfOrder=37, authorNames=LI G, NING C, MA Y, journalName=DNA Cell Biol, refType=null, unstructuredReference=LI G, NING C, MA Y, et al. miR-26b Promotes 3T3-L1 Adipocyte Differentiation Through Targeting PTEN. DNA Cell Biol. 2017; 36(8): 672-681., articleTitle=miR-26b Promotes 3T3-L1 Adipocyte Differentiation Through Targeting PTEN, refAbstract=null), Reference(id=1246459880400376440, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, doi=null, pmid=null, pmcid=null, year=2022, volume=26, issue=2, pageStart=260, pageEnd=265, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=娜日松, 孙亮, 赵振群, journalName=中国组织工程研究, refType=null, unstructuredReference=娜日松, 孙亮, 赵振群, 等. miR-26b调控脂肪酸结合蛋白4介导脂肪细胞分化的分子机制[J]. 中国组织工程研究, 2022, 26(2): 260-265., articleTitle=miR-26b调控脂肪酸结合蛋白4介导脂肪细胞分化的分子机制, refAbstract=null)], funds=[Fund(id=1246459874201194864, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, awardId=gzwjkj2021-1-353, language=EN, fundingSource=Guizhou Provincial Health Commission Science and Technology Fund Project(gzwjkj2021-1-353), fundOrder=null, country=null), Fund(id=1246459874268303732, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, awardId=gzwjkj2021-1-353, language=CN, fundingSource=贵州省卫生健康委科学技术基金项目(gzwjkj2021-1-353), fundOrder=null, country=null), Fund(id=1246459874364772732, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, awardId=KQYY-2021-2, language=EN, fundingSource=Guizhou Medical University Affiliated Stomatology Hospital Discipline Project(KQYY-2021-2), fundOrder=null, country=null), Fund(id=1246459874457047428, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, awardId=KQYY-2021-2, language=CN, fundingSource=贵州医科大学附属口腔医院学科项目(KQYY-2021-2), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1246459860804588515, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, xref=null, ext=[AuthorCompanyExt(id=1246459860817171428, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, companyId=1246459860804588515, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China), AuthorCompanyExt(id=1246459860825560037, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, companyId=1246459860804588515, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=贵州医科大学口腔医学院，贵州省贵阳市　550004)])], figs=[ArticleFig(id=1246459867255427321, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 1, caption=Morphology of stem cells from human exfoliated deciduous teeth obtained under inverted microscope, figureFileSmall=MhezAVolXSxdW+0JgBzyhw==, figureFileBig=WHNHfvc/QHK6of4VCosDKQ==, tableContent=null), ArticleFig(id=1246459867343507713, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图1, caption=倒置显微镜下观察人脱落乳牙牙髓干细胞形态

图注：图A为培养10 d时原代人脱落乳牙牙髓干细胞（标尺为500 μm）；B为第3代人脱落乳牙牙髓干细胞（标尺为100 μm）。

, figureFileSmall=MhezAVolXSxdW+0JgBzyhw==, figureFileBig=WHNHfvc/QHK6of4VCosDKQ==, tableContent=null), ArticleFig(id=1246459869038006543, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 2, caption=Results of flow cytometry identification of stem cells from human exfoliated deciduous teeth, figureFileSmall=3+RKqxaA90QmkT7mr7Iumw==, figureFileBig=8COShvtvPoAC5bH0JV0HNQ==, tableContent=null), ArticleFig(id=1246459870988357909, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图2, caption=人脱落乳牙牙髓干细胞的流式细胞术鉴定结果

图注：间充质干细胞标志物CD90、CD105阳性表达率分别为99.60%，99.80%，造血干细胞标志物CD34、CD45阳性表达率为0.084%，0.012%。

, figureFileSmall=3+RKqxaA90QmkT7mr7Iumw==, figureFileBig=8COShvtvPoAC5bH0JV0HNQ==, tableContent=null), ArticleFig(id=1246459871080632602, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 3, caption=Osteogenic and adipogenic differentiation ability of stem cells from human exfoliated deciduous teeth, figureFileSmall=AKseJB2ppZT2uohmKY/laQ==, figureFileBig=9OZjCW1QDCkdj9GyN5dZyA==, tableContent=null), ArticleFig(id=1246459871164518687, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图3, caption=人脱落乳牙牙髓干细胞的成骨、成脂分化潜能

图注：图A为成骨诱导28 d茜素红染色，可见钙结节（标尺为500 μm）；B为成脂诱导21 d油红O染色，可见脂滴（标尺为50 μm）。

, figureFileSmall=AKseJB2ppZT2uohmKY/laQ==, figureFileBig=9OZjCW1QDCkdj9GyN5dZyA==, tableContent=null), ArticleFig(id=1246459871260987685, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 4, caption=Neurogenic and angiogenic differentiation ability of stem cells from human exfoliated deciduous teeth, figureFileSmall=6j2yCG1/zRbM+nmgF/aUWg==, figureFileBig=zZN/lJWfALUlQGayA7DaBQ==, tableContent=null), ArticleFig(id=1246459871382622507, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图4, caption=人脱落乳牙牙髓干细胞的成神经、成血管分化潜能

图注：图A为RT-qPCR检测成神经相关基因的表达水平；B为RT-qPCR检测成血管相关基因的表达水平；C为免疫荧光检测βⅢ-tubulin及CD31蛋白的表达（标尺为100 μm）。aP < 0.05，bP < 0.01。

, figureFileSmall=6j2yCG1/zRbM+nmgF/aUWg==, figureFileBig=zZN/lJWfALUlQGayA7DaBQ==, tableContent=null), ArticleFig(id=1246459871487480112, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 5, caption=Expression levels of miR-26b during neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth, figureFileSmall=hjHCGwmJ+D55h2v5g0yWcw==, figureFileBig=+TcM6xxMBBX9/Esa6Ooscw==, tableContent=null), ArticleFig(id=1246459871651057975, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图5, caption=人脱落乳牙牙髓干细胞成神经分化及成血管分化过程中miR-26b的表达水平

图注：图A为成神经诱导分化过程中miR-26b的表达水平；B为成血管诱导分化过程中miR-26b的表达水平。aP < 0.01，bP < 0.001。

, figureFileSmall=hjHCGwmJ+D55h2v5g0yWcw==, figureFileBig=+TcM6xxMBBX9/Esa6Ooscw==, tableContent=null), ArticleFig(id=1246459871755915584, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 6, caption=Carboxyfluorescein (FAM) fluorescence expression and miR-26b cell transfection rate in stem cells from human exfoliated deciduous teeth, figureFileSmall=Krzt7AlljAfZlyv1RMOv9g==, figureFileBig=x/T0X7kcPteKM07vGhwuaQ==, tableContent=null), ArticleFig(id=1246459873345556809, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图6, caption=人脱落乳牙牙髓干细胞中羧基荧光素（FAM）荧光表达及miR-26b细胞转染率

图注：图A为人脱落乳牙牙髓干细胞转染miR-26b mimics 6 h后荧光显微镜下观察的明场图、荧光图（标尺为200 μm）；B为转染miR-26b mimics 48 h后，细胞内miR-26b的相对表达量（aP < 0.001）。

, figureFileSmall=Krzt7AlljAfZlyv1RMOv9g==, figureFileBig=x/T0X7kcPteKM07vGhwuaQ==, tableContent=null), ArticleFig(id=1246459873462997325, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 7, caption=Expression changes of neural-related genes and angiogenesis-related genes of stem cells from human exfoliated deciduous teeth in miR-26b overexpression detected by RT-qPCR, figureFileSmall=rSiZC2JcnWwzafan5cgLhw==, figureFileBig=bgOCSIJtna3F62+2ComHMg==, tableContent=null), ArticleFig(id=1246459873567854927, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图7, caption=RT-qPCR检测miR-26b过表达人脱落乳牙牙髓干细胞成神经和成血管相关基因的表达变化

图注：图A为转染miR-26b后人脱落乳牙牙髓干细胞成神经分化第7，14天成神经相关基因的表达；B为转染miR-26b后人脱落乳牙牙髓干细胞成血管分化第7，14天成血管相关基因的表达。aP < 0.01，bP < 0.001。

, figureFileSmall=rSiZC2JcnWwzafan5cgLhw==, figureFileBig=bgOCSIJtna3F62+2ComHMg==, tableContent=null), ArticleFig(id=1246459873630769493, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 8, caption=Western blot analysis showing changes in expression of neurogenic and angiogenic proteins in stem cells from human exfoliated deciduous teeth in miR-26b overexpression, figureFileSmall=M2xpU8fYlsfseYboNkrmzQ==, figureFileBig=euk97Q1BMIti1TVNXc7/Ng==, tableContent=null), ArticleFig(id=1246459873693684057, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图8, caption=Western blot检测miR-26b过表达人脱落乳牙牙髓干细胞成神经和成血管相关蛋白的表达变化

图注：aP < 0.05，bP < 0.01。

, figureFileSmall=M2xpU8fYlsfseYboNkrmzQ==, figureFileBig=euk97Q1BMIti1TVNXc7/Ng==, tableContent=null), ArticleFig(id=1246459873781764447, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Figure 9, caption=Fluorescence quantification of βIII-Tubulin and CD31 proteins in stem cells from human exfoliated deciduous teeth after miR-26b transfection for 14 days after neurogenesis and vasogenesis, figureFileSmall=zKytWVt/isVOz4dCyzY9nw==, figureFileBig=PY+TFe0NpU3AIWubeQARlg==, tableContent=null), ArticleFig(id=1246459873895010656, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=图9, caption=转染miR-26b后人脱落乳牙牙髓干细胞成神经和成血管诱导分化14 d βⅢ-Tubulin及CD31免疫荧光染色

图注：图A，C为CD31、βⅢ-Tubulin荧光表达（标尺为100 μm）；B，D为CD31、βⅢ-Tubulin蛋白的相对荧光强度，βⅢ-Tubulin过表达组的相对荧光强度约是阴性对照组的2.3倍，CD31过表达组的荧光强度约是阴性对照组的1.9倍。aP < 0.05，bP < 0.01。

, figureFileSmall=zKytWVt/isVOz4dCyzY9nw==, figureFileBig=PY+TFe0NpU3AIWubeQARlg==, tableContent=null), ArticleFig(id=1246459874004062564, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=EN, label=Table 1, caption=

Primer sequences

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列（5’-3’）
miR-26bF：GCC GCT TCA AGT AAT TCA GG
 R：TAT GGT TTT GAG GAC TGT GTA T
U6F：CTC GCT TCG GCA GCA CA
 R：AAC GCT TCA CGA ATT TGC GT
NSEF：GAA TTC ATG TCC ATA GAG AAG ATC TG
 R：TCT AGA AGA GGA ATC ACA GCA CAC TG
NestinF：CAA GGT GTT GTG CGA TGA CG
 R：GGG CTC TGA TCT CTG CAT CTA C
βⅢ-TubulinF：GGC CAA GGG TCA CTA CAC G
 R：GCA GTC CGC AGT TTT CAC ACT C
CD31F：ACG GAA GTT CAA GTG TCC TCA G
 R：GCT TTC CAC GGC ATC AGG GA
VEGFR2F：CTG CCT ACC TCA CCT GTT TCC
 R：CTG TCC GTC TGG TTG TCA TCT G
ANG-1F：TCG TGA GAG TAC GAC AGA CCA
 R：TCT CCG ACT TCA TGT TTT CCA C
GAPDHF：CAG GAG GCA TTG CTG ATG AT
 R：GAA GGC TGG GGC TCA TTT
), ArticleFig(id=1246459874083754346, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459853401641608, language=CN, label=表1, caption=

引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列（5’-3’）
miR-26bF：GCC GCT TCA AGT AAT TCA GG
 R：TAT GGT TTT GAG GAC TGT GTA T
U6F：CTC GCT TCG GCA GCA CA
 R：AAC GCT TCA CGA ATT TGC GT
NSEF：GAA TTC ATG TCC ATA GAG AAG ATC TG
 R：TCT AGA AGA GGA ATC ACA GCA CAC TG
NestinF：CAA GGT GTT GTG CGA TGA CG
 R：GGG CTC TGA TCT CTG CAT CTA C
βⅢ-TubulinF：GGC CAA GGG TCA CTA CAC G
 R：GCA GTC CGC AGT TTT CAC ACT C
CD31F：ACG GAA GTT CAA GTG TCC TCA G
 R：GCT TTC CAC GGC ATC AGG GA
VEGFR2F：CTG CCT ACC TCA CCT GTT TCC
 R：CTG TCC GTC TGG TTG TCA TCT G
ANG-1F：TCG TGA GAG TAC GAC AGA CCA
 R：TCT CCG ACT TCA TGT TTT CCA C
GAPDHF：CAG GAG GCA TTG CTG ATG AT
 R：GAA GGC TGG GGC TCA TTT
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miR-26b对人脱落乳牙牙髓干细胞向神经及血管分化的影响
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周绍兰 , 袁媛园 , 潘露 , 徐文 , 瞿姝熳
中国组织工程研究 | 研究原著 2025,29(36): 7769-7775
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中国组织工程研究 | 研究原著 2025, 29(36): 7769-7775
miR-26b对人脱落乳牙牙髓干细胞向神经及血管分化的影响
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周绍兰, 袁媛园, 潘露, 徐文, 瞿姝熳
作者信息
  • 贵州医科大学口腔医学院，贵州省贵阳市　550004

    • Zhou Shaolan, MS, Physician, School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China

    周绍兰，女，1996年生，贵州省贵阳市人，汉族，2023年贵州医科大学毕业，硕士，医师，主要从事牙体牙髓病学相关工作，以及牙髓干细胞方向研究工作。

通讯作者:

袁媛园，硕士，副主任医师，贵州医科大学口腔医学院，贵州省贵阳市　550004
Effect of miR-26b on neural and vascular differentiation in stem cells from human exfoliated deciduous teeth
Shaolan Zhou, Yuanyuan Yuan, Lu Pan, Wen Xu, Shuman Qu
Affiliations
  • School of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
出版时间: 2025-12-28 doi: 10.12307/2025.560
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摘要
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背景：

人脱落乳牙牙髓干细胞广泛应用于组织修复再生领域，但组织再生效果在实际应用中存在局限性。利用miRNA干预人脱落乳牙牙髓干细胞的定向分化是未来组织修复再生的重要发展方向。

目的：

探讨miR-26b对乳牙牙髓干细胞成神经及成血管分化能力的影响。

方法：

从人脱落乳牙中分离提取乳牙牙髓干细胞，并将其向神经及血管方向诱导分化，分别检测成神经标志物Nestin、NSE、βⅢ- Tubulin和成血管标志物CD31、VEGFR2、ANG-1及miR-26b的表达。然后将乳牙牙髓干细胞分为空白对照组、miR-26过表达组和阴性对照组，RT-qPCR、细胞免疫荧光染色及Western blot检测各组乳牙牙髓干细胞成神经及成血管诱导后相关标志物的表达变化。

结果与结论：

①乳牙牙髓干细胞具有多向分化潜能，能向成骨、成脂、成神经及成血管方向分化；②在乳牙牙髓干细胞成神经及成血管分化过程中miR-26b表达水平升高；③相较于空白对照组和阴性对照组，miR-26b过表达组乳牙牙髓干细胞成神经相关基因βⅢ-Tubulin、Nestin、NSE及成血管相关基因CD31、VEGFR2、ANG-1的mRNA表达显著升高（P < 0.01），βⅢ-Tubulin、Nestin及CD31、VEGFR2蛋白表达显著升高（P < 0.01）。以上结果表明，miR-26b过表达能促进人脱落乳牙牙髓干细胞成神经和成血管诱导分化。

乳牙牙髓干细胞  /  miR-26b  /  成神经分化  /  成血管分化  /  牙髓再生  /  工程化干细胞
BACKGROUND:

Stem cells from human exfoliated deciduous teeth are widely used in the field of tissue repair and regeneration, but the tissue regeneration effect has limitations in practical applications. Using miRNA to intervene in the directional differentiation of stem cells from human exfoliated deciduous teeth is an important development direction for tissue repair and regeneration in the future.

OBJECTIVE:

To investigate the effect of miR-26b on the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth.

METHODS:

Dental pulp stem cells were isolated and extracted from human exfoliated deciduous teeth, and induced to differentiate into nerves and blood vessels. The expressions of neurogenic markers Nestin, NSE, βIII-Tubulin, and angiogenic markers CD31, VEGFR2, ANG-1 and miR-26b were detected. Dental pulp stem cells were divided into blank control group, miR-26 overexpression group, and negative control group. RT-qPCR, cell immunofluorescence staining, and western blot assay were used to detect the expression changes of related markers of neurogenic and angiogenic induction of stem cells from human exfoliated deciduous teeth in each group.

RESULTS AND CONCLUSION:

(1) Stem cells from human exfoliated deciduous teeth had multi-directional differentiation potential and could differentiate into osteogenesis, adipogenesis, neurogenesis, and vasculogenesis. (2) The expression level of miR-26b increased during the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth. (3) Compared with the blank control group and negative control group, the mRNA expression of neuroblast-related genes βIII-Tubulin, Nestin, NSE and angiogenesis-related genes CD31, VEGFR2, and ANG-1 in stem cells from human exfoliated deciduous teeth in the miR-26b overexpression group was significantly increased (P < 0.01), βIII-Tubulin, Nestin, CD31, and VEGFR2 protein expression was significantly increased (P < 0.01). The above results show that overexpression of miR-26b can promote the neurogenic and angiogenic differentiation of stem cells from human exfoliated deciduous teeth.

stem cells from deciduous teeth  /  miR-26b  /  neurogenic differentiation  /  angiogenic differentiation  /  pulp regeneration  /  engineered stem cells
周绍兰, 袁媛园, 潘露, 徐文, 瞿姝熳. miR-26b对人脱落乳牙牙髓干细胞向神经及血管分化的影响. 中国组织工程研究, 2025 , 29 (36) : 7769 -7775 . DOI: 10.12307/2025.560
Shaolan Zhou, Yuanyuan Yuan, Lu Pan, Wen Xu, Shuman Qu. Effect of miR-26b on neural and vascular differentiation in stem cells from human exfoliated deciduous teeth[J]. Chinese Journal of Tissue Engineering Research, 2025 , 29 (36) : 7769 -7775 . DOI: 10.12307/2025.560
正文
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0　引言　Introduction
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牙髓根尖周病是口腔中多发性疾病，通常是由剧烈刺激（如龋齿、意外创伤或医源性原因）对牙髓的不可逆损伤所造成，可引起牙齿及颌面部剧烈的疼痛、肿胀甚至患牙缺失[1]。据统计全球患病率高达52%[2]，这意味着全世界一半人口都至少有一颗牙齿患有牙髓根尖周病。根管治疗是目前临床上牙髓根尖周病的主要治疗方法[3]，尽管现阶段根管治疗方法有了很大的改善，但在各种因素的影响下，仍存在较高的失败率[4]，且根管治疗后的牙齿会丢失原有的富含神经及血管的牙髓组织，丧失牙髓生理功能。近些年随着组织工程技术的发展，利用牙髓再生技术重建牙髓血管及神经并恢复其应有的防御以及感觉功能成为可能[5]，牙髓再生技术也愈发受到研究者的关注。
人脱落乳牙牙髓干细胞（stem cells from human exfoliated deciduous teeth，SHEDs）存在于乳牙牙髓组织，来源于外胚层神经嵴结构[6]，具有较其他来源间充质干细胞更强的神经向分化能力，同时SHEDs位于血管周围生态位，具有较强的成血管分化能力，是极具潜能的牙髓再生种子细胞，自从被发现以来一直是研究热点[7]。miRNA与干细胞增殖、迁移、分化等多种功能密切相关[8]。miR-26b是miRNA大家族的一员，过表达miR-26b可以促进内皮细胞的生长和存活，以增强血管内皮细胞增殖、迁移和血管形成能力[9]。此外，多项研究表明miR-26b参与调控间充质干细胞生物学特性，如miR-26促进SHEDs的增殖[10]。鉴于SHEDs具有出色的多向分化能力，以及miR-26b在间充质干细胞生物学中的重要调节作用，该实验在体外探究miR-26b对SHEDs成神经和成血管分化能力的影响，旨在为牙髓根尖周病的治疗提供新的策略。
1　材料和方法　Materials and methods
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1.1　设计
细胞生物学体外实验。
1.2　时间及地点
实验于2021年11月至2023年1月在贵州医科大学组织工程与干细胞实验中心及贵州医科大学附属医院临床医学研究中心完成。
1.3　材料
DMEM低糖培养基（Gibco，美国）；成骨诱导培养基和茜素红染色试剂盒（赛业，广州）；血管内皮细胞诱导培养基（Lonza，瑞士）；胎牛血清（Gibco，美国）；无血清神经诱导培养基（Gibco，美国）；B27（Gibco，美国）；表皮细胞生长因子（Pepro Tech，美国）；碱性成纤维细胞生长因子（Pepro Tech，美国）；成脂诱导培养基（Biological Industries，以色列）；Lipofectamine 2000（Invitrogen，美国）；miR-26b mimics miRNAs（吉玛制药，上海）；mimics对照（吉玛制药，上海）；反转录试剂盒（TaKaRa，日本）；RT-qPCR试剂盒（TaKaRa，日本）；Rabbit anti-Nestin（Proteintech，美国）；Rabbit anti-βⅢ-Tubulin（Affinity，美国）；Rabbit anti-CD31（Affinity，美国）；Rabbit anti-VEGFR2（Proteintech，美国）；Rabbit anti-GAPDH（Abcam，英国）；Cy3标记羊抗兔IgG（H+L）（Biosharp，广州）；ECL化学发光试剂盒（碧云天，上海）；BCA蛋白浓度测定试剂盒（碧云天，上海）；流式细胞仪（Beckman，美国）；SDS-PAGE凝胶配制试剂盒（碧云天，上海）；CFX96实时荧光定量PCR仪（BIO-RAD，美国）。
1.4　实验方法
1.4.1　SHEDs的分离与培养
在2021年11月至2022年3月期间，从贵州医科大学附属口腔医院收集6-10岁儿童因未能正常脱落而拔除的乳牙样本，共计4颗。首先用体积分数75%乙醇对这些乳牙进行消毒，随后用PBS反复清洗，以去除残留杂质。清洗完毕后，在超净台内将牙冠与牙根分开，取出牙髓腔内的牙髓，用手术剪将牙髓组织剪碎，转移至含Ⅰ型胶原酶的离心管中，37 ℃水浴消化30 min，1 000 r/min离心5 min，弃上清，加入含体积分数10%胎牛血清的DMEM培养基重悬，接种于T25培养瓶中，在37 ℃、体积分数5%CO2培养箱进行原代培养，待细胞生长融合率达到60%-80%时，加入0.25%胰蛋白酶消化，以1∶2比例传代，传代扩增至第3-5代，用于后续研究。
该研究的实施符合贵州医科大学的相关伦理要求，审批号为：2021伦申第（179）号，征求患儿及其监护人同意并签订知情同意书
1.4.2　SHEDs鉴定及多向分化能力检测
取第3代SHEDs，用胰酶消化后进行离心，加入5 mL PBS制备成单细胞悬液，以1 000 r/min离心5 min，弃去上清液，用PBS重悬细胞，将细胞浓度调整为1×109 L-1，分别加入5 μL含有FITC荧光标记的鼠抗人CD90、CD105抗体，以及含有PE荧光标记的鼠抗人CD34、CD45抗体，在4 ℃条件下避光孵育30 min，1 000 r/min离心5 min，去除上清液，用300 μL PBS重悬细胞，然后转移至流式细胞仪检测。
第3-5代SHEDs以每孔6×104个细胞密度接种于6孔板，待其生长融合至60%-70%时，成骨诱导组加入2 mL成骨诱导培养基，成脂诱导组加入2 mL成脂诱导培养基，每3 d换液1次，成脂诱导21 d进行油红O染色，成骨诱导28 d进行茜素红染色。
1.4.3　SHEDs成神经及成血管向诱导分化
第3-5代SHEDs以每孔3×104个细胞密度接种于6孔板，待细胞长至板底60%融合度时，成神经诱导组加入无血清神经诱导培养基（Neurobasal A培养基，2%B27添加剂、20 μg/L碱性成纤维细胞生长因子、20 μg/L表皮细胞生长因子及1%双抗），成血管诱导组加入2 mL血管内皮细胞诱导培养基，每2 d换液1次，在诱导7，14 d通过RT-qPCR检测成神经相关基因Nestin、βⅢ-Tubulin、NSE和成血管相关基因CD31、VEGFR2、ANG-1的表达，在诱导14 d通过细胞免疫荧光染色检测早期神经元标志物βⅢ-Tubulin及成血管相关蛋白CD31的表达。
1.4.4　细胞转染及分组
第3代SHEDs以每孔1.5×105个细胞密度接种于6孔板，当细胞融合约50%时开始转染，将带有羧基荧光素（FAM）标记的miR-26b mimics和miRNAs mimics按照说明转染至SHEDs。过表达组为转染miR-26b mimics的SHEDs，阴性对照组为转染miRNAs mimics的SHEDs，未进行转染的细胞设为空白对照组。转染6 h后，使用荧光显微镜观察荧光表达，然后继续在常规条件下培养24-48 h，进行后续诱导实验。
1.4.5　RT-qPCR检测转染效率
使用Trizol试剂提取各组SHEDs的总RNA，根据反转录试剂盒使用说明将RNA反转录为cDNA，采用SYBR Green法进行RT-qPCR扩增，PCR程序设置为：95 ℃ 30 s，95 ℃ 5 s，55 ℃ 30 s，72 ℃30 s，共40个循环。以U6作为内参基因，使用2-ΔΔCt法计算miR-26b的相对表达量。引物序列见表1。
1.4.6　RT-qPCR检测过表达miR-26b后SHEDs成神经及成血管相关基因的表达
第3-5代SHEDs以每孔3×104个细胞密度接种于6孔板，当细胞融合度达到70%时，分别加入无血清神经诱导培养基和血管内皮细胞诱导培养基，分别在第3，7，14天终止诱导，然后提取细胞总RNA，通过RT-qPCR检测miR-26b的表达水平。
转染SHEDs生长融合约70%时，空白对照组、过表达组及阴性对照组细胞进行成神经及成血管向诱导分化，分别在第7，14天终止诱导，提取总RNA，通过RT-qPCR检测成神经标志物Nestin、NSE、βⅢ-Tubulin以及成血管标志物CD31、VEGFR2、ANG-1 mRNA表达水平。引物序列见表1。
1.4.7　免疫荧光检测过表达miR-26b后SHEDs成神经及成血管相关蛋白的表达
转染SHEDs生长融合至70%-80%后，过表达组及阴性对照组细胞进行成神经及成血管向诱导分化，在第14天终止诱导。制备细胞爬片，PBS洗涤3次，每次2 min，40 g/L多聚甲醛固定15 min，PBS洗涤3次，每次2 min；0.1%Triton X-100通透15 min，PBS洗涤3次，每次3 min；用3% BSA在室温下封闭30 min，然后孵育不同的一抗（Rabbit anti-βⅢ-Tubulin、Rabbit anti-CD31，稀释比例1∶100），于4 ℃孵育过夜，PBS清洗3次，每次5 min；加入二抗，于室温孵育1 h，PBS洗3次，每次5 min；加入抗荧光淬灭剂封固液进行封固，在荧光显微镜下观察，使用Image J软件定量分析荧光强度。
1.4.8　Western blot检测过表达miR-26b后SHEDs成神经及成血管相关蛋白的表达
转染SHEDs生长融合至70%-80%后，空白对照组、过表达组及阴性对照组细胞进行成神经及血管向诱导分化，在第14天终止诱导，弃原培养基，PBS清洗，加入高效蛋白裂解液使细胞充分裂解，离心收集上清，利用BCA法测定蛋白浓度，加入蛋白缓冲液，煮沸变性，每个泳道加入等量蛋白，进行SDS-PAGE电泳，转膜，5%脱脂牛奶封闭1 h，加入一抗（Rabbit anti-βⅢ-Tubulin、Rabbit anti-Nestin、Rabbit anti-CD31、Rabbit anti-VEGFR2，稀释比例1∶3 000）4 ℃孵育过夜，洗膜，加入二抗（1∶3 000）常温孵育1 h，ECL曝光液曝光，保存图像，使用Image J进行定量分析。
1.5　主要观察指标
①SHEDs成神经及成血管诱导分化第7，14天成神经标志物Nestin、NSE、βⅢ-Tubulin以及成血管标志物CD31、VEGFR2、ANG-1的表达；②SHEDs诱导分化过程中miR-26b的表达；③过表达miR-26b后SHEDs成神经及成血管诱导分化第14天成神经标志物Nestin、NSE、βⅢ-Tubulin以及成血管标志物CD31、VEGFR2、ANG-1的表达；④过表达miR-26b后SHEDs成神经及成血管诱导分化第14天βⅢ-Tubulin及CD31蛋白荧光定量。
1.6　统计学分析
使用SPSS 21.0统计软件进行所有数据的处理分析，计量资料以表示，两组间比较采用Student's t test，P < 0.05为差异有显著性意义。文章统计学方法通过贵州医科大学生物统计学专家审核。
2　结果　Results
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2.1　SHEDs的培养和鉴定结果
原代培养3-7 d，显微镜下观察到细胞从组织块周边爬出，贴壁生长，多呈长梭形，以组织块为中心呈放射状向四周生长。细胞传代后2-4 h开始贴壁生长，两三天融合至80%，细胞形态较为均一，相互间多以平行排列的方式生长（图1）。流式细胞术检测SHEDs表面抗原CD34、CD45表达为阴性，CD90、CD105表达为阳性（图2）。成骨诱导28 d茜素红染色，镜下可观察到红染的矿化结节形成；成脂诱导21 d油红O染色，镜下可观察到红染发亮的圆形脂滴形成，脂滴大小不一（图3）。
2.2　SHEDs成神经及成血管分化潜能
在成神经及成血管诱导分化后成神经相关基因βⅢ-Tubulin、Nestin、NSE和成血管相关基因CD31、VEGFR2、ANG-1的表达逐步上调（P < 0.05）（图4A，B）。诱导14 d后免疫荧光染色可见神经元早期标志物βⅢ-Tubulin及成血管相关标志物CD31的表达（图4C）。
SHEDs成神经和成血管诱导过程中miR-26b的表达逐步上调（P < 0.01）（图5），这一结果提示miR-26b的差异表达可能与SHEDs成神经元样细胞及成血管内皮样细胞分化相关。
2.3　miR-26b过表达模型的验证
转染miR-26b mimics 6 h后，通过荧光显微镜观察到大部分细胞的胞体内有绿色荧光。转染48 h后，提取细胞总RNA，通过RT-qPCR检测miR-26b的表达变化。如图6所示，过表达组中miR-26b的表达量比对照组提高了约20倍（P < 0.001），说明miR-26b mimics可有效提高miR-26b在SHEDs中的表达。
2.4　过表达miR-26b促进SHEDs向神经及血管分化
在诱导分化第7，14天，与空白对照组、阴性对照组比较，过表达组成神经相关基因βⅢ-Tubulin、Nestin、NSE和成血管相关基因CD31、VEGFR2、ANG-1的mRNA水平均显著增加（P < 0.01）（图7）。
在诱导分化第14天，与空白对照组、阴性对照组比较，过表达组成神经相关蛋白βⅢ-Tubulin、Nestin和成血管相关蛋白CD31、VEGFR2的表达水平均显著增加（P < 0.01）（图8）。在诱导分化第14天，免疫荧光染色显示过表达组神经元早期标志物βⅢ-Tubulin及成血管相关标志物CD31的荧光强度较阴性对照组增强（图9）。
3　讨论　Discussion
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随着再生医学与组织工程研究的发展，利用干细胞实现牙髓再生已成为可行的研究方向[11-12]。牙髓是高度血管化和神经支配的组织，这两者的共同作用可能是促使牙髓再生成功的关键[13-14]。SHEDs起源于外胚间充质神经嵴，具有较强的成神经分化能力，研究发现SHEDs可通过多方面的神经再生活性促进脊髓损伤后的神经功能恢复[15]。不仅如此，SHEDs位于血管周围生态位，具有较强的成血管分化能力，不仅可以分化为血管内皮细胞，还可以分泌许多促进血管生成和神经发生的调节蛋白[16-18]。基于这一研究背景，该研究首先成功分离提取SHEDs，所提取的SHEDs具有与间充质干细胞相似的基本形态、免疫表型和生物学特性[19-21]，然后通过细胞因子成功诱导SHEDs成神经及成血管分化，检测到成神经相关因子及成血管相关因子的显著表达，与之前的研究结果一致[16,22-23]，提示SHEDs在成神经及成血管方面的良好开发潜能，SHEDs可能是牙髓再生的潜在种子细胞。
牙髓再生治疗中，干细胞的定植与分化受局部微环境的调控，miRNA作为一类短小的非编码RNA分子，广泛存在于生物体内，转录后miRNA可以与靶基因的mRNA结合，导致mRNA降解或者抑制其翻译，从而参与细胞的生长、分化、凋亡等生物过程[24-26]。有学者通过基因芯片筛选发现16个miRNAs在间充质干细胞趋化迁移中的差异表达，其中miR-26b的表达显著上调[27]，提示miR-26b在间充质干细胞中可能发挥着重要的作用。miR-26b是一种高度保守的miRNA，已有研究发现miR-26b的差异表达与多种细胞的增殖、分化密切相关，过表达miR-26b促进骨髓间充质干细胞的成骨及成软骨分化、促进脂肪间充质干细胞的成脂分化及胚胎干细胞的成神经元分化[28-29]。此外，课题组前期研究发现，miR-26b过表达促进SHEDs的增殖及迁移，因此推测miR-26b具有调控SHEDs定向分化的潜能[10]。
为验证miR-26b对SHEDs分化的影响，通过RT-qPCR检测miR-26b在成神经及成血管诱导分化过程中的表达，结果显示miR-26b的表达呈上调趋势且有明显时间依赖性，提示miR-26b参与SHEDs成神经及成血管分化的调控过程，这与之前的研究报道相一致[9,30]。为进一步验证miR-26b是否会影响SHEDs成神经和成血管分化能力，通过脂质体转染法上调SHEDs中miR-26b的表达量，并进一步诱导细胞向神经和血管方向分化。在miR-26b的作用下，与成神经及成血管密切相关的基因及蛋白表达均相应升高，证明miR-26b具有促进SHEDs成神经及成血管分化的能力。值得注意的是，相对于成神经相关因子的表达，成血管相关因子的表达总体上偏低，推测这可能与SHEDs来源于神经嵴，具有神经胚层的特性有关，这使得它们在神经分化方向上更具有潜力。以上结果提示miR-26b的调控可能成为一种潜在的治疗策略，用以促进牙髓组织再生和修复。
该研究证明miR-26b可增强SHEDs的成神经及成血管分化能力，但干细胞的分化过程是一个高度协调、精密调控的生物学过程，这个过程牵涉到复杂的分子网络，包括转录因子、靶基因和多种信号通路的协同作用。近期有学者发现，磷脂酰肌醇3激酶/蛋白激酶B（phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin，PI3K/Akt）信号通路与牙髓干细胞的增殖及迁移[31-32]、间充质干细胞的血管生成及神经分化密切相关[33-34]，它被认为是细胞内一个重要的信号传导通路。PI3K是一种磷脂激酶，活化的PI3K会将细胞膜上的PIP2转化为PIP3，当细胞内的PIP3水平增加时，Akt被磷酸化并激活，激活的Akt可以通过磷酸化一系列底物蛋白，参与调控细胞增殖、分化、运动和代谢等多种生物学过程。而miR-26b可通过抑制PI3K/Akt信号通路的负调控因子如PTEN间接激活该信号通路[35-36]，揭示miR-26b调控SHEDs分化的潜在机制。PTEN是磷酸酶，其主要功能是去除PIP3的磷酸基团，将其还原为PIP2，这个过程抑制了PI3K/Akt信号通路的活性，因此PTEN被认为是PI3K/Akt信号通路的重要负调控因子，可通过抑制PI3K/Akt信号通路的激活进而抑制细胞的分化潜能[37-39]。miR-26b对PENT具有抑制作用，PTEN是miR-26b的直接靶标，miR-26b可以结合到PTEN mRNA的3’ UTR，导致PTEN mRNA的降解，从而减少PTEN蛋白的表达[36-38]。结合以上学者的研究及该实验的结果，推测miR-26b上调可能抑制PTEN的表达，从而增强PI3K/Akt信号通路的活性，最终增强SHEDs成神经及成血管分化的能力。总体而言，miR-26b的过表达可以促进SHEDs向神经和血管方向分化，表现为成神经相关因子及成血管相关因子的mRNA和蛋白表达水平显著升高。这些结果为深入探究miR-26b在SHEDs分化过程中的调控机制提供重要线索。
综上所述，过表达miR-26b促进SHEDs向神经和血管分化。然而，由于体内环境及牙髓组织的成分相对复杂，成神经及成血管分化的调控因子众多，体外实验虽提示miR-26b具有促进SHEDs成神经及成血管的潜能，却仍存在局限性，有待后续体内实验进一步论证。此外，后续也将深入研究miR-26b是否通过PTEN负反馈激活PI3K/Akt信号通路从而促进SHEDs成神经及成血管分化。但总体而言，该研究证明了SHEDs在牙髓再生性治疗中的潜在价值，为临床治疗牙髓根尖周病提供新的契机。
基金
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  • 贵州省卫生健康委科学技术基金项目(gzwjkj2021-1-353)
  • 贵州医科大学附属口腔医院学科项目(KQYY-2021-2)
文献
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2025年第29卷第36期
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doi: 10.12307/2025.560
  • 接收时间：2024-06-19
  • 首发时间：2026-04-02
  • 出版时间：2025-12-28
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  • 收稿日期：2024-06-19
  • 修回日期：2024-11-11
  • 录用日期：2024-09-24
基金
Guizhou Provincial Health Commission Science and Technology Fund Project(gzwjkj2021-1-353)
贵州省卫生健康委科学技术基金项目(gzwjkj2021-1-353)
Guizhou Medical University Affiliated Stomatology Hospital Discipline Project(KQYY-2021-2)
贵州医科大学附属口腔医院学科项目(KQYY-2021-2)
作者信息
    贵州医科大学口腔医学院，贵州省贵阳市　550004

通讯作者:

袁媛园，硕士，副主任医师，贵州医科大学口腔医学院，贵州省贵阳市　550004
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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