转录因子NFIC在人根尖牙乳头干细胞分化中的作用及其机制研究
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摘要
干细胞在组织工程学中的运用将为牙髓/牙本质再生和生物性牙根的形成提供广阔的运用前景。根尖牙乳头干细胞（stem cells from the apical papilla，SCAPs）位于未发育完成的年轻恒牙的根尖部，是一种取自正在发育组织的成体间充质干细胞（mesenchymal stem cells，MSCs）。SCAPs具有多向分化的潜能，在特定培养液诱导下可形成类牙髓/牙本质，且被认为是牙根部成牙本质细胞的来源，最终形成牙根部牙本质。SCAPs与牙髓干细胞（dental pulp stem cells，DPSCs）相比，具有较强的成牙分化能力和较低的免疫原形，此特性被认为更适合运用于骨/牙体组织再生领域。
核转录因子NFIC（nuclear factor I-C）在调控牙根的发育中发挥了重要作用。敲除NFIC的小鼠，形成短小的磨牙牙根，而牙冠发育正常。鉴于NFIC是特异性调控牙根发育的信号分子，而SCAPs是牙根成牙本质细胞的来源，那么，NFIC在调控SCAPs分化中的作用及其机制如何，目前尚不清楚。
牙齿的发育是由一系列上皮和间充质相互作用而形成，众多的细胞因子参与了牙齿发育的调控。转化生长因子β（transforming growth factor-β，TGF-β）超家族，包括TGF-βs，骨形成蛋白（bone morphogenetic proteins，BMPs）和激活素类等相关蛋白，参与调节细胞增殖、分化及上皮间充质转换和胚胎发育等。研究发现NFIC通过抑制TGF-β1调控的基因表达，影响皮肤伤口的愈合；敲除NFIC后，小鼠异常的成牙本质细胞中TGF-βⅠ型受体和磷酸化的Smad2/3显著上调，提示，NFIC可能参与TGF-β信号通路，但是两者是在调控SCAPs分化中的作用机制尚不清楚。
本课题首先成功分离、培养和鉴定人根尖牙乳头干细胞。随后分别转染所构建的慢病毒NFIC真核表达载体或沉默NFIC的siRNA。通过体内、外实验观察NFIC对SCAPs增殖、分化的影响。最后，研究TGF-β1对SCAPs生物学特性及分化的影响，讨论NFIC与TGF-β1信号通路在SCAPs分化中的相互作用。为将来SCAPs在牙髓牙本质再生和生物性牙根方面的应用提供新的思路。
结果如下：
1.人根尖牙乳头感干细胞的分离、培养及鉴定
选取因正畸原因而拔除的年轻患者第三磨牙，分离培养人原代SCAPs,有限稀释法纯化获得单克隆的细胞；免疫组织化学染色及流式细胞仪鉴定间充质干细胞标记物STRO-1等；成骨诱导、成脂诱导实验证实细胞的多向分化能力。
2.转录因子NFIC促进SCAPs分化能力
构建NFIC慢病毒真核表达载体plenti-NFIC后，与沉默NFIC的siRNA分别转染SCAPs。过表达NFIC还促进SCAPs的增殖能力、ALP活性和成骨/牙分化能力。此外，NFIC还不同程度地增强矿化基因标记物ALP、OCN和Col.I的mRNA；蛋白质印迹免疫检测技术也证实NFIC上调DSP蛋白水平。而沉默NFIC,则明显抑制SCAPs矿化能力及矿化基因ALP、OCN和Col.I的表达。此外，过表达NFIC增强脂滴的形成和成脂标记物CCAAT增强结合蛋白（CCAAT/enhancer binding protein）C/EBP-β、C/EBP-δ和过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor-y，PPAR-γ）的表达。
体内研究进一步证实：过表达NFIC的SCAPs细胞复合胶原/煅烧牛骨(calcinedbovine bone，CBB)材料植入免疫缺陷型小鼠的皮下12周后，可促进形成类成牙本质细胞和牙本质样结构。
3.转录因子NFIC参与TGF-β1信号通路对SCAPs的调控
不同浓度TGF-β1均抑制SCAPs增殖和体外矿化结节形成，并下调矿化基因的表达，而分别应用TGF-β1Ⅰ型受体抑制剂SB431542和Smad3的抑制剂SIS3阻断TGF-β信号通路后，可部分逆转TGF-β1对SCAPs增殖和分化的抑制作用。TGF-β1抑制NFIC蛋白的表达，过表达NFIC减弱TGF-β1对SCAPs矿化能力的抑制作用，而沉默NFIC则增强了TGF-β1对SCAPs成牙/骨的分化能力。实验结果显示NFIC参与TGF-β1信号通路对SCAPs的生物学调控。
综上所述，本研究通过体内/外实验证实NFIC可以促进根尖牙乳头干细胞的增殖和分化能力；而TGF-β1则起抑制作用；且NFIC参与了TGF-β1对根尖牙乳头干细胞分化特性的调控。本实验结果为阐述NFIC在调控SCAPs定向分化中的重要作用；同时为进一步研究SCAPs在牙髓牙本质再生和生物学牙根的组织工程研究提供了新的研究思路。
The use of stem cells in tissue engineering strongly extends the range of itsapplications in dental pulp/dentin regeneration or the bioroot for the future. Stem cellsderived from the apical papilla (SCAPs) are a population of mesenchymal stem cells(MSCs) residing in root apex of incompletely developed teeth. SCAPs appear to have acapacity of multi-lineage dentinogenic, especially dentinogenic differentiation when underdefined culture conditions. SCAPs are thought to be the major souce for primaryodontoblasts which are responsible for the formation of root dentin. As a distinct source ofpotent dental stem/progenitor cells, SCAPs show a greater dentinogenic potential andweakly immunogenic compared with dental pulp stem cells (DPSCs), which might be of significance for their application in bone/dental tissue engineering.
Nuclear factor I-C (NFIC) was reported as a critical regulator in root formation.Disruption of NFIC caused developed short molar roots contained aberrant odontoblastsand abnormal dentin formation, but normal crowns in mice. Studies have reported thatNFIC played a critical role in root development and SCAPs were the source ofodontoblasts of root. However, the effects and mechanisms of NFIC on the differentiationof SCAPs have not yet been reported.
Tooth root formation is mediated through a series of epithelial-mesenchymalinteractions regulated by several factors. The transforming growth factor-β (TGF-β)superfamily, including TGF-βs, bone morphogenetic protein, activins andinhibins,regulates cell proliferation, cell differentiation, the epithelial-to-mesenchymal transitionand embryonic development and so on. Reports have confirmed NFIC affected the normalprogression of the skin wound healing process by inhibiting the level of TGF-β.Disruption of NFIC, both the expression of TGF-β-RI and the phosphorylation of Smad2/3increased during odontoblast, which revealed the interaction between NFIC and TGF-βsignaling pathway. However, the exact mechanism for the regulation and interaction ofNFIC and TGF-β on the differentiation of SCAPs are still unknown.
In the present study, we isolated, expanded and identificated SCAPs from the apicalpapilla. The pLenti6.3/v5-NFIC plasmid encoding full-length NFIC or NFIC silence bysi-RNA were constructed and transfected into SCAPs respectively. Then, the effects ofNFIC on the proliferation and differentiation of SCAPs were subsequently determined invitro and in vivo. In addition, we also evaluated the effects of TGF-β1on the proliferativecapacity and differentiation potential of SCAPs. The crosstalk between NFIC and TGF-β1were further determined. These will facilitate the application of SCAPs in pulp/dentinregeneration and bioroot formation.Main results
1. Isolation, expandation and identification of SCAPs.
Human third molars with developing roots were collected due to orthodontic reasons.The extraction procedure was approved by Institutional Review Board of the Fourth Military Medical University and performed with the informed consent of the patients.Single cell suspensions of SCAPs were obtained by limiting dilution procedures.Immunocytochemical staining and flow cytometry-based cell sorting showed that the cellsderived from apical papilla contained mesenchymal stem cell populations. Besides, theisolated cells had the ability of osteo/odontogenic and adipogenic differentiation, whengrew under defined culture conditions.
2. The effects of NFIC on proliferation and differentiation of SCAPs and in vitro.
The pLenti6.3/v5-NFIC plasmid encoding full-length NFIC or NFIC silence bysi-RNA were constructed and transfected into SCAPs respectively. The proliferation, ALPactivity and osteo/odontogenic differentiation capacity of SCAPs were increased byoverexpression of NFIC. Besides, NFIC upregulated the mRNA levels of alkalinephosphatase (ALP), osteocalcin (OCN) and collagen typeⅠ(CoL.I), as well as dentinsialoprotein (DSP) protein which were analyzed by western blot. In contrast, knockdownof NFIC blocked the mineralization of SCAPs and downregulated the expression ofodontogenic-related markers ALP, OCN and CoL.I. Additionally, the lipid dropletsformation and the adipogenic differentiation markers (CCAAT/enhancer binding proteinbeta C/EBP-β, CCAAT/enhancer binding protein delta C/EBP-δ and peroxisomeproliferator-activated receptor gamma PPARγ) were further induced by NFIC.
Consistently, in vivo results further demonstrated that NFIC promoted the odontoblastor dentin like tissues regeneration integrating with the collagen and (calcined bovinebone，CBB) biomaterials in immunocompromised mice after12weeks.
3. Involvement of NFIC in the biological effects of TGF-β1on SCAPs
TGF-β1inhibited the prolifiration of SCAPs and mineral nodule formation indose-dependant manner. The mRNA levels of ALP, OCN and CoL.I were alldownregulated by TGF-β1. Results indicated that preincubated with the inhibitors ofTGF-β/Smad signaling (SB431542or SIS3) attenuated the suppressive effect of TGF-β1on the differention of SCAPs. TGF-β1inhibited NFIC protein level. In addition,overexpression of NFIC inhibited the effects of TGF-β1on SCAPs while knockdown of TGF-β1on SCAPs.
In summary, results suggested that NFIC enhanced the proliferation and mineralizeddifferentiation of SCAPs both in vitro and in vivo, mechanically, we further found thatNFIC may be a key regulator for the inhibitory effect of TGF-β1in calcified noduleformation and osteo/dentinogenic differentiation. Taken together, current study providedvaluable evidence for the application of NFIC in the pulp/dentin regeneration and biorootformation in the future.
核转录因子NFIC（nuclear factor I-C）在调控牙根的发育中发挥了重要作用。敲除NFIC的小鼠，形成短小的磨牙牙根，而牙冠发育正常。鉴于NFIC是特异性调控牙根发育的信号分子，而SCAPs是牙根成牙本质细胞的来源，那么，NFIC在调控SCAPs分化中的作用及其机制如何，目前尚不清楚。
牙齿的发育是由一系列上皮和间充质相互作用而形成，众多的细胞因子参与了牙齿发育的调控。转化生长因子β（transforming growth factor-β，TGF-β）超家族，包括TGF-βs，骨形成蛋白（bone morphogenetic proteins，BMPs）和激活素类等相关蛋白，参与调节细胞增殖、分化及上皮间充质转换和胚胎发育等。研究发现NFIC通过抑制TGF-β1调控的基因表达，影响皮肤伤口的愈合；敲除NFIC后，小鼠异常的成牙本质细胞中TGF-βⅠ型受体和磷酸化的Smad2/3显著上调，提示，NFIC可能参与TGF-β信号通路，但是两者是在调控SCAPs分化中的作用机制尚不清楚。
本课题首先成功分离、培养和鉴定人根尖牙乳头干细胞。随后分别转染所构建的慢病毒NFIC真核表达载体或沉默NFIC的siRNA。通过体内、外实验观察NFIC对SCAPs增殖、分化的影响。最后，研究TGF-β1对SCAPs生物学特性及分化的影响，讨论NFIC与TGF-β1信号通路在SCAPs分化中的相互作用。为将来SCAPs在牙髓牙本质再生和生物性牙根方面的应用提供新的思路。
结果如下：
1.人根尖牙乳头感干细胞的分离、培养及鉴定
选取因正畸原因而拔除的年轻患者第三磨牙，分离培养人原代SCAPs,有限稀释法纯化获得单克隆的细胞；免疫组织化学染色及流式细胞仪鉴定间充质干细胞标记物STRO-1等；成骨诱导、成脂诱导实验证实细胞的多向分化能力。
2.转录因子NFIC促进SCAPs分化能力
构建NFIC慢病毒真核表达载体plenti-NFIC后，与沉默NFIC的siRNA分别转染SCAPs。过表达NFIC还促进SCAPs的增殖能力、ALP活性和成骨/牙分化能力。此外，NFIC还不同程度地增强矿化基因标记物ALP、OCN和Col.I的mRNA；蛋白质印迹免疫检测技术也证实NFIC上调DSP蛋白水平。而沉默NFIC,则明显抑制SCAPs矿化能力及矿化基因ALP、OCN和Col.I的表达。此外，过表达NFIC增强脂滴的形成和成脂标记物CCAAT增强结合蛋白（CCAAT/enhancer binding protein）C/EBP-β、C/EBP-δ和过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor-y，PPAR-γ）的表达。
体内研究进一步证实：过表达NFIC的SCAPs细胞复合胶原/煅烧牛骨(calcinedbovine bone，CBB)材料植入免疫缺陷型小鼠的皮下12周后，可促进形成类成牙本质细胞和牙本质样结构。
3.转录因子NFIC参与TGF-β1信号通路对SCAPs的调控
不同浓度TGF-β1均抑制SCAPs增殖和体外矿化结节形成，并下调矿化基因的表达，而分别应用TGF-β1Ⅰ型受体抑制剂SB431542和Smad3的抑制剂SIS3阻断TGF-β信号通路后，可部分逆转TGF-β1对SCAPs增殖和分化的抑制作用。TGF-β1抑制NFIC蛋白的表达，过表达NFIC减弱TGF-β1对SCAPs矿化能力的抑制作用，而沉默NFIC则增强了TGF-β1对SCAPs成牙/骨的分化能力。实验结果显示NFIC参与TGF-β1信号通路对SCAPs的生物学调控。
综上所述，本研究通过体内/外实验证实NFIC可以促进根尖牙乳头干细胞的增殖和分化能力；而TGF-β1则起抑制作用；且NFIC参与了TGF-β1对根尖牙乳头干细胞分化特性的调控。本实验结果为阐述NFIC在调控SCAPs定向分化中的重要作用；同时为进一步研究SCAPs在牙髓牙本质再生和生物学牙根的组织工程研究提供了新的研究思路。
The use of stem cells in tissue engineering strongly extends the range of itsapplications in dental pulp/dentin regeneration or the bioroot for the future. Stem cellsderived from the apical papilla (SCAPs) are a population of mesenchymal stem cells(MSCs) residing in root apex of incompletely developed teeth. SCAPs appear to have acapacity of multi-lineage dentinogenic, especially dentinogenic differentiation when underdefined culture conditions. SCAPs are thought to be the major souce for primaryodontoblasts which are responsible for the formation of root dentin. As a distinct source ofpotent dental stem/progenitor cells, SCAPs show a greater dentinogenic potential andweakly immunogenic compared with dental pulp stem cells (DPSCs), which might be of significance for their application in bone/dental tissue engineering.
Nuclear factor I-C (NFIC) was reported as a critical regulator in root formation.Disruption of NFIC caused developed short molar roots contained aberrant odontoblastsand abnormal dentin formation, but normal crowns in mice. Studies have reported thatNFIC played a critical role in root development and SCAPs were the source ofodontoblasts of root. However, the effects and mechanisms of NFIC on the differentiationof SCAPs have not yet been reported.
Tooth root formation is mediated through a series of epithelial-mesenchymalinteractions regulated by several factors. The transforming growth factor-β (TGF-β)superfamily, including TGF-βs, bone morphogenetic protein, activins andinhibins,regulates cell proliferation, cell differentiation, the epithelial-to-mesenchymal transitionand embryonic development and so on. Reports have confirmed NFIC affected the normalprogression of the skin wound healing process by inhibiting the level of TGF-β.Disruption of NFIC, both the expression of TGF-β-RI and the phosphorylation of Smad2/3increased during odontoblast, which revealed the interaction between NFIC and TGF-βsignaling pathway. However, the exact mechanism for the regulation and interaction ofNFIC and TGF-β on the differentiation of SCAPs are still unknown.
In the present study, we isolated, expanded and identificated SCAPs from the apicalpapilla. The pLenti6.3/v5-NFIC plasmid encoding full-length NFIC or NFIC silence bysi-RNA were constructed and transfected into SCAPs respectively. Then, the effects ofNFIC on the proliferation and differentiation of SCAPs were subsequently determined invitro and in vivo. In addition, we also evaluated the effects of TGF-β1on the proliferativecapacity and differentiation potential of SCAPs. The crosstalk between NFIC and TGF-β1were further determined. These will facilitate the application of SCAPs in pulp/dentinregeneration and bioroot formation.Main results
1. Isolation, expandation and identification of SCAPs.
Human third molars with developing roots were collected due to orthodontic reasons.The extraction procedure was approved by Institutional Review Board of the Fourth Military Medical University and performed with the informed consent of the patients.Single cell suspensions of SCAPs were obtained by limiting dilution procedures.Immunocytochemical staining and flow cytometry-based cell sorting showed that the cellsderived from apical papilla contained mesenchymal stem cell populations. Besides, theisolated cells had the ability of osteo/odontogenic and adipogenic differentiation, whengrew under defined culture conditions.
2. The effects of NFIC on proliferation and differentiation of SCAPs and in vitro.
The pLenti6.3/v5-NFIC plasmid encoding full-length NFIC or NFIC silence bysi-RNA were constructed and transfected into SCAPs respectively. The proliferation, ALPactivity and osteo/odontogenic differentiation capacity of SCAPs were increased byoverexpression of NFIC. Besides, NFIC upregulated the mRNA levels of alkalinephosphatase (ALP), osteocalcin (OCN) and collagen typeⅠ(CoL.I), as well as dentinsialoprotein (DSP) protein which were analyzed by western blot. In contrast, knockdownof NFIC blocked the mineralization of SCAPs and downregulated the expression ofodontogenic-related markers ALP, OCN and CoL.I. Additionally, the lipid dropletsformation and the adipogenic differentiation markers (CCAAT/enhancer binding proteinbeta C/EBP-β, CCAAT/enhancer binding protein delta C/EBP-δ and peroxisomeproliferator-activated receptor gamma PPARγ) were further induced by NFIC.
Consistently, in vivo results further demonstrated that NFIC promoted the odontoblastor dentin like tissues regeneration integrating with the collagen and (calcined bovinebone，CBB) biomaterials in immunocompromised mice after12weeks.
3. Involvement of NFIC in the biological effects of TGF-β1on SCAPs
TGF-β1inhibited the prolifiration of SCAPs and mineral nodule formation indose-dependant manner. The mRNA levels of ALP, OCN and CoL.I were alldownregulated by TGF-β1. Results indicated that preincubated with the inhibitors ofTGF-β/Smad signaling (SB431542or SIS3) attenuated the suppressive effect of TGF-β1on the differention of SCAPs. TGF-β1inhibited NFIC protein level. In addition,overexpression of NFIC inhibited the effects of TGF-β1on SCAPs while knockdown of TGF-β1on SCAPs.
In summary, results suggested that NFIC enhanced the proliferation and mineralizeddifferentiation of SCAPs both in vitro and in vivo, mechanically, we further found thatNFIC may be a key regulator for the inhibitory effect of TGF-β1in calcified noduleformation and osteo/dentinogenic differentiation. Taken together, current study providedvaluable evidence for the application of NFIC in the pulp/dentin regeneration and biorootformation in the future.
引文
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