CN113813403A - Mettl3在制备修复牙髓损伤的药物中的用途 - Google Patents
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Abstract
本发明公开了METTL3或METTL3基因表达促进剂在制备修复牙髓损伤的药物中的用途。本发明通过对牙髓干细胞向成牙本质样细胞方向分化的研究，揭示了METTL3牙髓细胞分化过程中的作用，并结合大鼠意外穿髓模型验证过表达METTL3腺相关病毒直接盖髓的治疗效果证实，将促进METTL3表达的化学制剂或生物制剂作为促进修复性牙本质形成的盖髓剂，有助于损伤修复及保存牙髓活力。
Description
技术领域
本发明具体涉及METTL3在制备修复牙髓损伤的药物中的用途。
背景技术
在临床上深龋，外伤等牙髓损伤的情况下，常进行直接或间接盖髓治疗以促进牙髓修复，但目前尚无盖髓剂能够达到理想的保髓效果。目前常用于活髓保存治疗的盖髓材料包括氢氧化钙类及MTA类制剂，但这两种盖髓剂的目标都是促进硬组织生成，在临床应用中存在一定缺陷性。氢氧化钙类制剂会造成局部强碱性微环境，诱发牙髓细胞坏死，形成的继发性牙本质不连续且封闭性差；MTA类制剂虽然促矿化作用优于氢氧化化钙，但医疗成本高，临床操作性较差。
牙髓组织具有感受外界刺激及一定的自我保护能力，但由于髓腔的特殊环境，感染无法引流且易于扩散，损伤发展形成牙髓及根尖周病变。牙髓及根尖周病变是牙体牙髓科临床最常见的疾病。根据选取人群不同，患病率从27％-70％均有报道。广州市18～74岁城乡居民牙髓根尖周病的患病率是28.42﹪，并有随年龄增大而逐渐增高的趋势。根管治疗是目前治疗牙髓及根尖周病变的主要手段，虽然该方法已较大程度的延长了患牙的功能性存留时间，但因完全摘除牙髓组织，会导致牙齿抗折能力显著降低，咀嚼功能下降，影响年轻恒牙的牙根发育，具有显著的局限性。因此，在牙髓损伤早期仍有活力时，调控牙髓干细胞分化，促进修复性牙本质的形成，有助于损伤修复及保存牙髓活力。
METTL3基因(Ensembl:ENSG00000165819)编码MT-A的70kda亚单位，MT-A是N6腺苷甲基转移酶的一部分，这种酶参与真核细胞mRNAs内部腺苷残基的转录后甲基化，形成N6甲基腺苷。
目前还没关于METTL3能促进牙髓损伤后的牙髓细胞成牙本质分化的报道。
发明内容
为解决上述问题，本发明提供了METTL3或METTL3基因表达促进剂在制备修复牙髓损伤的药物中的用途。
METTL3基因表达促进剂：是指可以使得机体的METTL3基因表达水平提高的任何物质，比如，METTL3基因过表达质粒或METTL3基因过表达腺相关病毒。
进一步地，所述药物是促进牙髓细胞成牙本质分化的药物。
进一步地，所述药物是提高ALP基因表达水平的药物。
进一步地，所述药物是提高DMP-1基因表达水平的药物。
进一步地，所述药物是提高DSPP基因表达水平的药物。
本发明还提供了一种用于修复牙髓损伤的组合物，它是以METTL3表达因子促进剂为活性成分，加上药学上可接受的辅料制备而成的制剂。
进一步地，所述制剂为外用制剂。
进一步地，所述外用制剂为膏剂、散剂或溶液剂。
更进一步地，所述膏剂为盖髓剂。
本发明METTL3表达因子促进剂在制备修复牙髓损伤的药物中的用途，通过牙髓干细胞向成牙本质样细胞方向分化情况的研究，揭示了METTL3在牙髓干细胞分化过程中的作用，并结合大鼠意外穿髓模型验证过表达METTL3腺相关病毒直接盖髓的治疗效果证实，将促进METTL3表达的化学制剂或生物制剂作为促进修复性牙本质形成的盖髓剂，有助于损伤修复及保存牙髓活力。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1过表达METTL3的牙髓干细胞中分化标志基因ALP,RUNX2,DMP-1,DSPP的基因表达水平改变
图2过表达METTL3的牙髓干细胞碱性磷酸酶和茜素红染色变化
图3METTL3过表达组H&E染色图
图4阴性对照组H&E染色图
具体实施方式
实施例1METTL3对牙髓干细胞体外成牙本质向分化能力的影响
一、方法
1)牙髓干细胞的制备
临床收集18-25岁患者因阻生拔除的健康完整的第三磨牙(经本人及家属知情同意)，机械分离牙髓组织，胶原酶消化，取组织块培养得原代牙髓干细胞，将原代牙髓干细胞传代至F 3-5代，得到用于后续实验的牙髓干细胞。
2)构建METTL3过表达的牙髓干细胞
将FLAG-METTL3片段(TGGGCTGCAGGTCGACTCTAGAGGATCCCCGGGTACCGGTCGCCACCATGTCGGACACGTGGAGCTCTATCCAGGCCCACAAGAAGCAGCTGGACTCTCTGCGGGAGAGGCTGCAGCGGAGGCGGAAGCAGGACTCGGGGCACTTGGATCTACGGAATCCAGAGGCAGCATTGTCTCCAACCTTCCGTAGTGACAGCCCAGTGCCTACTGCACCCACCTCTGGTGGCCCTAAGCCCAGCACAGCTTCAGCAGTTCCTGAATTAGCTACAGATCCTGAGTTAGAGAAGAAGTTGCTACACCACCTCTCTGATCTGGCCTTAACATTGCCCACTGATGCTGTGTCCATCTGTCTTGCCATCTCCACGCCAGATGCTCCTGCCACTCAAGATGGGGTAGAAAGCCTCCTGCAGAAGTTTGCAGCTCAGGAGTTGATTGAGGTAAAGCGAGGTCTCCTACAAGATGATGCACATCCTACTCTTGTAACCTATGCTGACCATTCCAAGCTCTCTGCCATGATGGGTGCTGTGGCAGAAAAGAAGGGCCCTGGGGAGGTAGCAGGGACTGTCACAGGGCAGAAGCGGCGTGCAGAACAGGACTCGACTACAGTAGCTGCCTTTGCCAGTTCGTTAGTCTCTGGTCTGAACTCTTCAGCATCGGAACCAGCAAAGGAGCCAGCCAAGAAATCAAGGAAACATGCTGCCTCAGATGTTGATCTGGAGATAGAGAGCCTTCTGAACCAACAGTCCACTAAGGAACAACAGAGCAAGAAGGTCAGTCAGGAGATCCTAGAGCTATTAAATACTACAACAGCCAAGGAACAATCCATTGTTGAAAAATTTCGCTCTCGAGGTCGGGCCCAAGTGCAAGAATTCTGTGACTATGGAACCAAGGAGGAGTGCATGAAAGCCAGTGATGCTGATCGACCCTGTCGCAAGCTGCACTTCAGACGAATTATCAATAAACACACTGATGAGTCTTTAGGTGACTGCTCTTTCCTTAATACATGTTTCCACATGGATACCTGCAAGTATGTTCACTATGAAATTGATGCTTGCATGGATTCTGAGGCCCCTGGCAGCAAAGACCACACGCCAAGCCAGGAGCTTGCTCTTACACAGAGTGTCGGAGGTGATTCCAGTGCAGACCGACTCTTCCCACCTCAGTGGATCTGTTGTGATATCCGCTACCTGGACGTCAGTATCTTGGGCAAGTTTGCAGTTGTGATGGCTGACCCACCCTGGGATATTCACATGGAACTGCCCTATGGGACCCTGACAGATGATGAGATGCGCAGGCTCAACATACCCGTACTACAGGATGATGGCTTTCTCTTCCTCTGGGTCACAGGCAGGGCCATGGAGTTGGGGAGAGAATGTCTAAACCTCTGGGGGTATGAACGGGTAGATGAAATTATTTGGGTGAAGACAAATCAACTGCAACGCATCATTCGGACAGGCCGTACAGGTCACTGGTTGAACCATGGGAAGGAACACTGCTTGGTTGGTGTCAAAGGAAATCCCCAAGGCTTCAACCAGGGTCTGGATTGTGATGTGATCGTAGCTGAGGTTCGTTCCACCAGTCATAAACCAGATGAAATCTATGGCATGATTGAAAGACTATCTCCTGGCACTCGCAAGATTGAGTTATTTGGACGACCACACAATGTGCAACCCAACTGGATCACCCTTGGAAACCAACTGGATGGGATCCACCTACTAGACCCAGATGTGGTTGCACGGTTCAAGCAAAGGTACCCAGATGGTATCATCTCTAAACCTAAGAATTTAGGTATGGACTACAAGGATGACGATGACAAGGATTACAAAGACGACGATGATAAGGACTATAAGGATGATGACGACAAATGAGCTAGCCTGTGGAATGTGTGTCAGTTAGGGTGTGGAAAGTCCCC)亚克隆至GV358载体，AgeI/AgeI酶切，获得稳定的过表达慢病毒；转染步骤1)培养的牙髓干细胞，建立METTL3过表达的牙髓干细胞。
3)牙髓干细胞成牙本质向分化
以矿化诱导液(10mmol/Lβ甘油磷酸钠、10-8mol/L地塞米松、50mg/L维生素C)对步骤2)的METTL3过表达牙髓干细胞和阴性对照的牙髓干细胞进行成牙本质分化诱导，用碱性磷酸酶染色法检测过表达METTL3及阴性对照的牙髓干细胞碱性磷酸酶活性，并以茜素红染色验证矿化结节的产生。实时荧光定量PCR检测分化标志基因的表达。
二、结果
牙髓干细胞中分化标志基因ALP,RUNX2,DMP-1,DSPP的基因表达水平结果见图1，碱性磷酸酶染色和茜素红染色结果见图2。
从图1和图2可见：相比于阴性对照组，METTL3过表达组的碱性磷酸酶活性及矿化结节明显增多，且分化标志基因ALP,DMP-1,DSPP的基因表达明显上调，由此可见，METTL3促进牙髓干细胞成牙本质向分化。
实施例2METTL3对动物直接盖髓模型中牙髓损伤修复的影响
通过模拟临床上发生意外穿髓的情况下直接盖髓治疗，观察牙髓损伤修复进程中METTL3过表达的治疗作用。
一、方法
1)建立牙髓损伤动物模型
取2月龄SD大鼠，以双侧下颌磨牙为实验对象进行自身对照。以装有1/4小球钻的涡轮机于下颌第一磨牙咬合面备洞，至可观察到透红时，以无菌根管挫尖端暴露牙髓，无菌棉球压迫止血，得牙髓损伤大鼠模型；
2)盖髓治疗
将步骤1)牙髓损伤大鼠20只分为两组，以浸有阴性对照腺相关病毒的明胶海绵直接盖髓作为对照组，以浸有METTL3过表达腺相关病毒明胶海绵直接盖髓为实验组，玻璃离子垫底，树脂充填窝洞，常规培养4周；
其中，METTL3过表达腺相关病毒是腺相关病毒(AAV)根据METTL3的cDNA序列(CACTTTGGCAAAGAATTGGGATTCGAACATCGATTGAATTCGGTACCGGAATTCGGAACTGGAGGTGGAGGTAGTGGAATGGATCCCGCCACCATGTCGGACACGTGGAGCTCTATCCAGGCCCATAAGAAACAACTGGACTCGCTTCGCGAGAGACTGCAGCGGCGGCGGAAGCAGGACTCTGGGCACTTGGACTTAAGGAATCCAGAAGCAGCACTGTCCCCAACCTTCCGTAGTGATAGCCCAGTGCCTACTGCCCCTACCTCTAGTGGCCCTAAGCCCAGCACAACGTCTATAGTCCCTGAATTAGCTACAGACCCTGAGTTAGAGAAGAAGTTGCTACACCACCTCTCAGATCTCGCCTTAACCTTGCCCACTGATGCTGTATCCATCCGTCTTGCCATCTCTACGCCAGATGCACCTGCCACTCAAGATGGGGTAGAAAGCCTTCTACAGAAATTTGCTGCCCAGGAGTTGATTGAGGTAAAGCGAGGTCTCCTACAAGATGACGCACATCCCACTCTCGTAACCTATGCTGACCACTCCAAGCTGTCTGCCATGATGGGGGCTGTGGCAGAAAAGAAAGGCCTTGGAGAGGCAGCAGGGACTATCACAGGGCAGAAACGGCGTGCAGAGCAGGACTTGACTACAGTGGCTACCTTTACCAGCTCTTTAGCATCTGGTCTGGGCTCTTCAACATCAGAACCAGCTAAGGAGCCAGCTAAGAAATCAAGGAAGCACGCTGCCTCAGATGTTGACCTGGAGATAGAAAGTCTTTTGAACCAACAGTCAACTAAGGAACAGCAGAGCAAGAAGGTCAGTCAGGAGATCCTAGAGCTATTAAATACCACAACAGCCAAGGAACAGTCCATTGTTGAAAAGTTCCGCTCTCGAGGTCGGGCCCAGGTGCAAGAATTTTGTGACTATGGGACCAAGGAAGAGTGCATGAAAGCCAGTGACGCTGATCGGCCTTGTCGCAAGCTGCACTTCAGACGGATTATCAACAAGCACACTGATGAGTCTTTAGGTGATTGCTCTTTCCTGAACACCTGCTTCCACATGGACACCTGCAAGTATGTCCACTATGAAATTGACGCCTGTGTGGATTCTGAGAGTCCTGGCAGCAAGGAGCACATGCCGAGCCAGGAGCTTGCTCTTACACAGAGCGTTGGGGGCGACTCCAGTGCAGACCGACTCTTTCCACCCCAGTGGATCTGTTGTGATATCCGCTACCTGGACGTCAGTATCTTGGGCAAATTTGCAGTTGTGATGGCTGACCCACCTTGGGATATTCACATGGAGCTACCGTATGGGACGTTAACAGATGACGAGATGCGCAGGCTCAATATACCAGTACTACAGGATGATGGCTTTCTTTTCCTCTGGGTCACAGGCAGGGCCATGGAATTGGGCAGAGAATGTCTGAACCTCTGGGGTTACGAGCGGGTGGACGAGATCATCTGGGTGAAGACCAATCAGCTGCAGCGCATCATCAGGACAGGCCGGACAGGCCACTGGCTGAACCACGGGAAGGAGCACTGCTTGGTTGGTGTCAAAGGAAATCCCCAAGGCTTCAACCAGGGTCTGGATTGCGATGTGATTGTAGCTGAGGTTCGTTCCACCAGTCACAAACCAGATGAAATATATGGCATGATTGAGAGACTGTCCCCTGGCACCCGAAAGATTGAGTTATTTGGACGACCACACAATGTGCAGCCCAACTGGATTACTCTTGGAAACCAACTGGATGGGATACACCTTCTGGACCCAGATGTGGTTGCCCGGTTTAAGCACAGGTATCCAGATGGTGTCATCTCTAAACCTAAGAACTTAGCTAGCGACTACAAGGATGACGATGACAAGGATTACAAAGACGACGATGATAAGGACTATAAGGATGAT)采用GV411载体，BamHI/NheI酶切进行载体质粒构建及测序验证，载体转染工具细胞，收集得到AAV粗病毒后采用密度梯度离心或阴离子交换柱纯化进行浓缩和纯化，并通过qPCR进行病毒基因拷贝的滴度检测后用于动物实验。
3)检测相关指标
取对照组和实验组大鼠牙髓下颌磨牙，进行H&E染色分析牙髓断面炎细胞浸润区域大小，继发性牙本质桥厚度及牙本质小管形态，以此确定牙髓损伤修复进程。
二、结果
H&E染色扫描结果见图3～图4。从结果可见：阴性对照组的牙髓损伤处下方未见明显新生牙本质的形成，牙髓损伤区域敞开，牙髓细胞排列不规则，有明显血管增生或炎性细胞浸润，显示牙髓组织炎性损伤；METTL3过表达组的牙髓损伤处下方可见纤维状新生牙本质的形成，牙髓细胞排列规则，无明显血管增生或炎性细胞浸润，显示继发性牙本质形成及牙髓的损伤修复。对比两组H&E染色可以看出，METTL3过表达有助于修复性牙本质形成，并促进牙髓牙本质复合体的再生。
综上，通过牙髓干细胞向成牙本质样细胞方向分化情况的研究，揭示了，METTL3在牙髓干细胞分化过程中的作用，并结合大鼠意外穿髓模型验证过表达METTL3腺相关病毒直接盖髓的治疗效果证实，将促进METTL3表达的化学制剂或生物制剂作为促进修复性牙本质形成的盖髓剂，有助于损伤修复及保存牙髓活力。
SEQUENCE LISTING
<110> 南方医科大学口腔医院
<120> METTL3在制备修复牙髓损伤的药物中的用途
<130> GYKH1937-2021P0113098CCR4
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 1912
<212> DNA
<213> 人工序列（artificial sequence）
<400> 1
tgggctgcag gtcgactcta gaggatcccc gggtaccggt cgccaccatg tcggacacgt 60
ggagctctat ccaggcccac aagaagcagc tggactctct gcgggagagg ctgcagcgga 120
ggcggaagca ggactcgggg cacttggatc tacggaatcc agaggcagca ttgtctccaa 180
ccttccgtag tgacagccca gtgcctactg cacccacctc tggtggccct aagcccagca 240
cagcttcagc agttcctgaa ttagctacag atcctgagtt agagaagaag ttgctacacc 300
acctctctga tctggcctta acattgccca ctgatgctgt gtccatctgt cttgccatct 360
ccacgccaga tgctcctgcc actcaagatg gggtagaaag cctcctgcag aagtttgcag 420
ctcaggagtt gattgaggta aagcgaggtc tcctacaaga tgatgcacat cctactcttg 480
taacctatgc tgaccattcc aagctctctg ccatgatggg tgctgtggca gaaaagaagg 540
gccctgggga ggtagcaggg actgtcacag ggcagaagcg gcgtgcagaa caggactcga 600
ctacagtagc tgcctttgcc agttcgttag tctctggtct gaactcttca gcatcggaac 660
cagcaaagga gccagccaag aaatcaagga aacatgctgc ctcagatgtt gatctggaga 720
tagagagcct tctgaaccaa cagtccacta aggaacaaca gagcaagaag gtcagtcagg 780
agatcctaga gctattaaat actacaacag ccaaggaaca atccattgtt gaaaaatttc 840
gctctcgagg tcgggcccaa gtgcaagaat tctgtgacta tggaaccaag gaggagtgca 900
tgaaagccag tgatgctgat cgaccctgtc gcaagctgca cttcagacga attatcaata 960
aacacactga tgagtcttta ggtgactgct ctttccttaa tacatgtttc cacatggata 1020
cctgcaagta tgttcactat gaaattgatg cttgcatgga ttctgaggcc cctggcagca 1080
aagaccacac gccaagccag gagcttgctc ttacacagag tgtcggaggt gattccagtg 1140
cagaccgact cttcccacct cagtggatct gttgtgatat ccgctacctg gacgtcagta 1200
tcttgggcaa gtttgcagtt gtgatggctg acccaccctg ggatattcac atggaactgc 1260
cctatgggac cctgacagat gatgagatgc gcaggctcaa catacccgta ctacaggatg 1320
atggctttct cttcctctgg gtcacaggca gggccatgga gttggggaga gaatgtctaa 1380
acctctgggg gtatgaacgg gtagatgaaa ttatttgggt gaagacaaat caactgcaac 1440
gcatcattcg gacaggccgt acaggtcact ggttgaacca tgggaaggaa cactgcttgg 1500
ttggtgtcaa aggaaatccc caaggcttca accagggtct ggattgtgat gtgatcgtag 1560
ctgaggttcg ttccaccagt cataaaccag atgaaatcta tggcatgatt gaaagactat 1620
ctcctggcac tcgcaagatt gagttatttg gacgaccaca caatgtgcaa cccaactgga 1680
tcacccttgg aaaccaactg gatgggatcc acctactaga cccagatgtg gttgcacggt 1740
tcaagcaaag gtacccagat ggtatcatct ctaaacctaa gaatttaggt atggactaca 1800
aggatgacga tgacaaggat tacaaagacg acgatgataa ggactataag gatgatgacg 1860
acaaatgagc tagcctgtgg aatgtgtgtc agttagggtg tggaaagtcc cc 1912
<210> 2
<211> 1902
<212> DNA
<213> 腺相关病毒（Adeno associated virus）
<400> 2
cactttggca aagaattggg attcgaacat cgattgaatt cggtaccgga attcggaact 60
ggaggtggag gtagtggaat ggatcccgcc accatgtcgg acacgtggag ctctatccag 120
gcccataaga aacaactgga ctcgcttcgc gagagactgc agcggcggcg gaagcaggac 180
tctgggcact tggacttaag gaatccagaa gcagcactgt ccccaacctt ccgtagtgat 240
agcccagtgc ctactgcccc tacctctagt ggccctaagc ccagcacaac gtctatagtc 300
cctgaattag ctacagaccc tgagttagag aagaagttgc tacaccacct ctcagatctc 360
gccttaacct tgcccactga tgctgtatcc atccgtcttg ccatctctac gccagatgca 420
cctgccactc aagatggggt agaaagcctt ctacagaaat ttgctgccca ggagttgatt 480
gaggtaaagc gaggtctcct acaagatgac gcacatccca ctctcgtaac ctatgctgac 540
cactccaagc tgtctgccat gatgggggct gtggcagaaa agaaaggcct tggagaggca 600
gcagggacta tcacagggca gaaacggcgt gcagagcagg acttgactac agtggctacc 660
tttaccagct ctttagcatc tggtctgggc tcttcaacat cagaaccagc taaggagcca 720
gctaagaaat caaggaagca cgctgcctca gatgttgacc tggagataga aagtcttttg 780
aaccaacagt caactaagga acagcagagc aagaaggtca gtcaggagat cctagagcta 840
ttaaatacca caacagccaa ggaacagtcc attgttgaaa agttccgctc tcgaggtcgg 900
gcccaggtgc aagaattttg tgactatggg accaaggaag agtgcatgaa agccagtgac 960
gctgatcggc cttgtcgcaa gctgcacttc agacggatta tcaacaagca cactgatgag 1020
tctttaggtg attgctcttt cctgaacacc tgcttccaca tggacacctg caagtatgtc 1080
cactatgaaa ttgacgcctg tgtggattct gagagtcctg gcagcaagga gcacatgccg 1140
agccaggagc ttgctcttac acagagcgtt gggggcgact ccagtgcaga ccgactcttt 1200
ccaccccagt ggatctgttg tgatatccgc tacctggacg tcagtatctt gggcaaattt 1260
gcagttgtga tggctgaccc accttgggat attcacatgg agctaccgta tgggacgtta 1320
acagatgacg agatgcgcag gctcaatata ccagtactac aggatgatgg ctttcttttc 1380
ctctgggtca caggcagggc catggaattg ggcagagaat gtctgaacct ctggggttac 1440
gagcgggtgg acgagatcat ctgggtgaag accaatcagc tgcagcgcat catcaggaca 1500
ggccggacag gccactggct gaaccacggg aaggagcact gcttggttgg tgtcaaagga 1560
aatccccaag gcttcaacca gggtctggat tgcgatgtga ttgtagctga ggttcgttcc 1620
accagtcaca aaccagatga aatatatggc atgattgaga gactgtcccc tggcacccga 1680
aagattgagt tatttggacg accacacaat gtgcagccca actggattac tcttggaaac 1740
caactggatg ggatacacct tctggaccca gatgtggttg cccggtttaa gcacaggtat 1800
ccagatggtg tcatctctaa acctaagaac ttagctagcg actacaagga tgacgatgac 1860
aaggattaca aagacgacga tgataaggac tataaggatg at 1902
Claims (10)
1.METTL3或METTL3基因表达促进剂在制备修复牙髓损伤的药物中的用途。
2.根据权利要求1所述的用途，其特征在于，所述METTL3基因表达促进剂包括但不限于METTL3基因过表达质粒或METTL3基因过表达腺相关病毒。
3.根据权利要求1所述的用途，其特征在于，所述药物是促进牙髓细胞成牙本质分化的药物。
4.根据权利要求3所述的用途，其特征在于，所述药物是提高ALP基因表达水平的药物。
5.根据权利要求3所述的用途，其特征在于，所述药物是提高DMP-1基因表达水平的药物。
6.根据权利要求3所述的用途，其特征在于，所述药物是提高DSPP基因表达水平的药物。
7.一种用于修复牙髓损伤的组合物，其特征在于，它是以METTL3基因表达因子促进剂为活性成分，加上药学上可接受的辅料制备而成的制剂。
8.根据权利要求7所述的组合物，其特征在于：所述METTL3基因表达促进剂包括但不限于METTL3基因过表达质粒或METTL3基因过表达腺相关病毒。
9.根据权利要求7或8所述的组合物，其特征在于：所述制剂为外用制剂；所述外用制剂为膏剂、散剂或溶液剂。
10.根据权利要求9所述的组合物，其特征在于：所述膏剂为盖髓剂。
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