牙胚微环境诱导真皮和牙龈来源成体干细胞分化的实验研究
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摘要
组织工程化牙齿研究的关键在于:获取来源丰富且具有成牙潜能的种子细胞,使其在适宜的成牙微环境下发育、分化。牙齿器官的发育需要釉质形成所需的牙源性上皮细胞和形成牙髓牙本质复合体的牙源性间充质细胞共同来完成,而牙源性种子细胞在成体中来源十分有限,因此,寻找取材方便、扩增容易、特性稳定且符合伦理道德的成体干细胞作为种子细胞是目前牙齿再生研究的热点之一。本实验分离培养了SD大鼠掌趾部皮肤真皮多能干细胞和牙龈粘膜上皮干细胞,并对其干细胞生物学特性进行了鉴定,在此基础上利用同种属发育早期牙胚细胞分泌的信号分子在体外模拟牙胚发育的微环境,探讨皮肤真皮多能干细胞向牙源性间充质细胞分化的能力,以及牙龈粘膜上皮干细胞向牙源性上皮细胞方向分化的可行性,并为非牙源性成体干细胞向成牙细胞分化所需的微环境提供实验方案,为筛选和诱导组织工程牙齿种子细胞提供研究参考。取得的主要研究结果如下:
1.不同时期牙齿胚基发育能力和微环境变化的研究
观察SD大鼠胚胎帽状期和出生后钟状末期牙胚及其各部分解离组织块在肾被膜下的生长发育情况,初步明确不同发育时期牙胚在肾被膜下的发育能力,结果表明发育早期牙胚的碎组织具有更强的牙齿形成能力,所形成的牙齿结构较完整正确。进一步将原代培养后帽状期和钟状末期牙胚离散细胞植入肾被膜下发育,结果显示帽状期牙胚离散细胞可形成组织工程化牙胚样结构,帽状期牙间充质离散细胞可形成牙本质牙髓复合体结构,其组织结构和形态均较钟状末期牙胚离散细胞和牙间充质离散细胞所形成的牙齿结构规则、完整。
由此得出,离散的牙上皮细胞和间充质细胞之间信号网络所提供的微环境可完善和充分地指导牙齿的继续发育,提示来自这两种发育时期牙胚的成牙微环境所包含的特异性信息可由单个细胞携带并发挥作用。
2.牙胚细胞微环境诱导皮肤真皮多能干细胞分化的研究
为了探讨牙胚细胞构建的微环境对于非牙源性间充质干细胞的诱导能力,本实验采用贴壁细胞培养法和有限稀释法培养SD大鼠皮肤真皮多能干细胞,利用发育早期牙胚细胞分泌的信号分子在体外模拟成牙微环境,观察对皮肤真皮多能干细胞增殖分化的影响。结果显示,以出生1d的SD仔鼠掌趾部皮肤为组织来源,可培养获得具有间充质干细胞生物学特性的皮肤真皮多能干细胞。在此基础上,体外利用牙胚细胞条件培养液诱导培养皮肤真皮多能干细胞,可促进其增殖和矿化,并实现了向牙源性间充质细胞方向的表型转化。为进一步观察诱导后细胞的体内分化能力,使用牙胚细胞条件培养液预处理煅烧牙本质管支架材料后,再将皮肤真皮多能干细胞复合于支架材料内部移植于裸鼠皮下,培养6w后观察到帽状期牙胚细胞条件培养液诱导组移植物在材料内部可形成一些质地均匀的矿化组织,进一步免疫组织化学染色显示矿化组织可表达BSP、DSP,具有类似牙本质样矿化的特性。钟状末期牙胚细胞条件培养液诱导组移植物中仅有少量矿化组织生成,BSP表达阳性,DSP表达阴性提示为骨样组织。
以上结果提示,帽状期牙胚细胞条件培养液所提供的成牙微环境可在体外和体内促进皮肤真皮多能干细胞的牙向分化,经帽状期牙胚细胞条件培养液预处理的煅烧牙本质管具有一定的诱导分化作用,可促进皮肤真皮多能干细胞向牙本质样矿化方向分化;而钟状末期牙胚细胞条件培养液仅可诱导细胞发生表型的暂时转化,诱导后的细胞在体内不能继续分化为具有功能的牙源性细胞,同时也说明仅仅依靠支架材料上负载的牙胚发育信号分子不能完全实现皮肤真皮多能干细胞向成牙本质细胞有序分化并构建牙髓牙本质复合体。非牙源性干细胞在体内牙向分化更需要持续且稳定存在的成牙微环境,如何将种子细胞、微环境和支架材料三者有效结合来构建组织工程化牙齿还需进一步研究。
3.牙胚细胞微环境诱导牙龈上皮干细胞分化的研究
利用出生4w SD大鼠牙龈粘膜培养牙龈上皮细胞,结果显示其中部分细胞呈克隆样生长,细胞增殖较缓、大部分细胞处于静止期,且CK14和β1-整合素表达阳性,具有典型的上皮干细胞特征。在此基础上,利用第二部分实验结果确定的帽状期牙胚细胞微环境构建细胞间相互诱导模式,体外诱导培养牙龈上皮干细胞,结果表明牙胚细胞与牙龈上皮干细胞有序接触共培养后可促进牙龈上皮干细胞增殖,在表型和基因水平表达特异的成釉相关蛋白;而牙胚细胞条件培养液和混合接触共培养诱导后的牙龈上皮细胞表型改变不明显。将诱导后的细胞以细胞团的形式移植同种异体鼠肾被膜下观察,结果显示诱导后的细胞在体内不能形成典型的釉质样矿化结构。
本研究结果显示,分离培养的牙龈上皮干细胞可在体外牙胚细胞提供的成牙微环境中向牙源性上皮细胞方向分化,同时进一步肯定了帽状期牙胚细胞所分泌的可溶性信号分子在成体干细胞牙向分化过程中的重要诱导作用。体内结果提示建立良好的上皮-间充质接触从而使上皮和间充质之间形成储存信号与介导信号传递的基底膜是牙上皮结构发育的重要条件。
The crucial point of tooth engineering is to obtain plenty candidate cells that have odontogenic potential and capable of development and differentiation in suitable microenvironment. Tooth development follows the concept of epithelial–mesenchymal interactions which require dental epithelial cells to differentiate into enamel as well as dental mesenchymal cells to develop into dentin-pulp complex. However, the limitation of dental-derived stem cells obscured the approach of the tooth regeneration. What is evident is that work in this field is urgently needed as the ability to isolate large numbers of adult stem cells which biopsied easily, proliferate efficiently, and have distinct identity without ethic conflicts would be of great interest scientifically particularly with respect to future therapeutic applications and the developing discipline of tooth engineering. In this paper, the recombined microenvironment from developmental teeth was used to provide odontogenic niche for candidate cells. Using the mimic odontogenic environment, the potential of the differentiation and morphogenesis of skin dermal-derived multipotent stem cells (DMSCs) and gingival epithelial stem cells (GESCs) was assessed. Meanwhile, the results provide an effective strategy for the odontogenic induction of non-dental adult stem cells and present evidences of sorting candidate cells for tooth regeneration research.
Part 1. Potential of tooth germ tissues from different development stages
We investigated the ectopic growth and development of 14-day embryonic and one-day postnatal molar germ-related tissues from Sprague-Dawley rats in renal capsules. The HE results demonstrated that the tooth germ-related tissues at cap stage that could form regular tooth structures developed much better than those at late bell stage. To further confirm the development potential of dissociated cells of tooth germs at the two stages, we implanted tooth cells and dental mesenchymal cells of the two stages of molar germs in renal capsules, respectively. The results shows that dissociated tooth germ cells at cap stage formed better tooth structures than those at late bell stage; and the mesenchymal cells at cap stage produced dentin-pulp complex. However, tooth germ cells and papilla cells at late bell stage generated irregular bone-dental-like structures.
In conclusion, dissociated dental epithelial and mesenchymal cells could recapitulate the embryonic tooth germ environment to favour normal tooth development, indicating that the dissociated single dental cell retained genetic signaling network which is necessary for odontogenesis.
Part 2. Differentiation of tooth germ microenvironment induced skin dermal multipotent stem cells
In present study we sought to explore the possibility of utilizing DMSCs easily available from skin tissue for odontogenic induction. Using the limiting-dilution technique, colony-forming cell population was isolated and characterized by proliferative activity and multilineage differentiation potential. By in vitro exposure to conditioned medium of embryonic and neonatal tooth germ cells in culture, the proliferation and mineralization activity of DMSCs was elevated while the embryonic tooth germ cell conditioned medium (ETGC-CM) produced more significant effects. Meanwhile, TGC-CM treated DMSCs phenocopied the odontoblasts as indicated by specific lineage markers. To further examine the in vivo development potential of induced DMSCs, TGC-CM pretreated scaffolds were loaded with treated DMSCs. Following in vivo subcutaneous transplantation, ETGC-CM treated DMSCs were capable of producing blocks of dentin-like matrix as proved by positive staining of BSP and DSP. While NTGC-CM treated DMSCs formed fewer mineral nodules inside the scaffolds which were morphologically and immunochemically identified as bone-like tissues.
These observations suggest that under the sufficiently potent inductive microenvironment, DMSCs can be directed into odontoblast-like lineage cells. Our results further posit that the extrinsic niche where cells reside in is continuously required to maintain odontogenic differentiation. More suitable and optimal odontogenic microenvironment need to be further exploited and will be of substantial utility in the context of choosing non-dental adult stem cells for tooth regeneration. Our work highlights the potential utility of DMSCs as an alternative candidate cell source in hopes of developing more practical strategy of tooth regeneration research and offering promising opportunities for therapeutic approach.
Part 3. Differentiation of tooth germ microenvironment induced gingival epithelial stem cells
In this study, we isolated and characterized gingival epithelial cell population, from which existed a subpopulation that have stem cell properties, such as colony forming ability, slow cell cycle, capacity for self-renewal, and undifferentiated state as indicated by positive staining ofβ1-Integrin and CK14. To evaluate their odontogenic differentiation potential, cap stage tooth germ development niche was chosen to establish different patterns of cell interaction including TGC-CM, ordered and mixed contact co-culture. The data accumulated here showed that the ordered contact co-culture systems can effectively induce GESCs toward the ameloblasts phenotype, while the TGC-CM and mixed contact co-culture could not effectively initiate the odontogenic differentiation of GESCs. Following in vivo transplantation as cell pellets, there was no sufficient experimental evidence showed that induced GESCs could form enamel-like tissues.
Taken together, it confirms the critical role of molecular signals in the microenvironment of cap stage tooth germ. Furthermore, the results also indicate that in order to accomplish tooth regeneration, it will be best if the natural process of epithelial–mesenchymal interactions of teeth embryonic development can be reiterated in vitro or in vivo. Accordingly, growth factors and their reservation and transmission through a substrate to anchor the candidate cells could be achieved as natural tooth initiation and morphogenesis.
1.不同时期牙齿胚基发育能力和微环境变化的研究
观察SD大鼠胚胎帽状期和出生后钟状末期牙胚及其各部分解离组织块在肾被膜下的生长发育情况,初步明确不同发育时期牙胚在肾被膜下的发育能力,结果表明发育早期牙胚的碎组织具有更强的牙齿形成能力,所形成的牙齿结构较完整正确。进一步将原代培养后帽状期和钟状末期牙胚离散细胞植入肾被膜下发育,结果显示帽状期牙胚离散细胞可形成组织工程化牙胚样结构,帽状期牙间充质离散细胞可形成牙本质牙髓复合体结构,其组织结构和形态均较钟状末期牙胚离散细胞和牙间充质离散细胞所形成的牙齿结构规则、完整。
由此得出,离散的牙上皮细胞和间充质细胞之间信号网络所提供的微环境可完善和充分地指导牙齿的继续发育,提示来自这两种发育时期牙胚的成牙微环境所包含的特异性信息可由单个细胞携带并发挥作用。
2.牙胚细胞微环境诱导皮肤真皮多能干细胞分化的研究
为了探讨牙胚细胞构建的微环境对于非牙源性间充质干细胞的诱导能力,本实验采用贴壁细胞培养法和有限稀释法培养SD大鼠皮肤真皮多能干细胞,利用发育早期牙胚细胞分泌的信号分子在体外模拟成牙微环境,观察对皮肤真皮多能干细胞增殖分化的影响。结果显示,以出生1d的SD仔鼠掌趾部皮肤为组织来源,可培养获得具有间充质干细胞生物学特性的皮肤真皮多能干细胞。在此基础上,体外利用牙胚细胞条件培养液诱导培养皮肤真皮多能干细胞,可促进其增殖和矿化,并实现了向牙源性间充质细胞方向的表型转化。为进一步观察诱导后细胞的体内分化能力,使用牙胚细胞条件培养液预处理煅烧牙本质管支架材料后,再将皮肤真皮多能干细胞复合于支架材料内部移植于裸鼠皮下,培养6w后观察到帽状期牙胚细胞条件培养液诱导组移植物在材料内部可形成一些质地均匀的矿化组织,进一步免疫组织化学染色显示矿化组织可表达BSP、DSP,具有类似牙本质样矿化的特性。钟状末期牙胚细胞条件培养液诱导组移植物中仅有少量矿化组织生成,BSP表达阳性,DSP表达阴性提示为骨样组织。
以上结果提示,帽状期牙胚细胞条件培养液所提供的成牙微环境可在体外和体内促进皮肤真皮多能干细胞的牙向分化,经帽状期牙胚细胞条件培养液预处理的煅烧牙本质管具有一定的诱导分化作用,可促进皮肤真皮多能干细胞向牙本质样矿化方向分化;而钟状末期牙胚细胞条件培养液仅可诱导细胞发生表型的暂时转化,诱导后的细胞在体内不能继续分化为具有功能的牙源性细胞,同时也说明仅仅依靠支架材料上负载的牙胚发育信号分子不能完全实现皮肤真皮多能干细胞向成牙本质细胞有序分化并构建牙髓牙本质复合体。非牙源性干细胞在体内牙向分化更需要持续且稳定存在的成牙微环境,如何将种子细胞、微环境和支架材料三者有效结合来构建组织工程化牙齿还需进一步研究。
3.牙胚细胞微环境诱导牙龈上皮干细胞分化的研究
利用出生4w SD大鼠牙龈粘膜培养牙龈上皮细胞,结果显示其中部分细胞呈克隆样生长,细胞增殖较缓、大部分细胞处于静止期,且CK14和β1-整合素表达阳性,具有典型的上皮干细胞特征。在此基础上,利用第二部分实验结果确定的帽状期牙胚细胞微环境构建细胞间相互诱导模式,体外诱导培养牙龈上皮干细胞,结果表明牙胚细胞与牙龈上皮干细胞有序接触共培养后可促进牙龈上皮干细胞增殖,在表型和基因水平表达特异的成釉相关蛋白;而牙胚细胞条件培养液和混合接触共培养诱导后的牙龈上皮细胞表型改变不明显。将诱导后的细胞以细胞团的形式移植同种异体鼠肾被膜下观察,结果显示诱导后的细胞在体内不能形成典型的釉质样矿化结构。
本研究结果显示,分离培养的牙龈上皮干细胞可在体外牙胚细胞提供的成牙微环境中向牙源性上皮细胞方向分化,同时进一步肯定了帽状期牙胚细胞所分泌的可溶性信号分子在成体干细胞牙向分化过程中的重要诱导作用。体内结果提示建立良好的上皮-间充质接触从而使上皮和间充质之间形成储存信号与介导信号传递的基底膜是牙上皮结构发育的重要条件。
The crucial point of tooth engineering is to obtain plenty candidate cells that have odontogenic potential and capable of development and differentiation in suitable microenvironment. Tooth development follows the concept of epithelial–mesenchymal interactions which require dental epithelial cells to differentiate into enamel as well as dental mesenchymal cells to develop into dentin-pulp complex. However, the limitation of dental-derived stem cells obscured the approach of the tooth regeneration. What is evident is that work in this field is urgently needed as the ability to isolate large numbers of adult stem cells which biopsied easily, proliferate efficiently, and have distinct identity without ethic conflicts would be of great interest scientifically particularly with respect to future therapeutic applications and the developing discipline of tooth engineering. In this paper, the recombined microenvironment from developmental teeth was used to provide odontogenic niche for candidate cells. Using the mimic odontogenic environment, the potential of the differentiation and morphogenesis of skin dermal-derived multipotent stem cells (DMSCs) and gingival epithelial stem cells (GESCs) was assessed. Meanwhile, the results provide an effective strategy for the odontogenic induction of non-dental adult stem cells and present evidences of sorting candidate cells for tooth regeneration research.
Part 1. Potential of tooth germ tissues from different development stages
We investigated the ectopic growth and development of 14-day embryonic and one-day postnatal molar germ-related tissues from Sprague-Dawley rats in renal capsules. The HE results demonstrated that the tooth germ-related tissues at cap stage that could form regular tooth structures developed much better than those at late bell stage. To further confirm the development potential of dissociated cells of tooth germs at the two stages, we implanted tooth cells and dental mesenchymal cells of the two stages of molar germs in renal capsules, respectively. The results shows that dissociated tooth germ cells at cap stage formed better tooth structures than those at late bell stage; and the mesenchymal cells at cap stage produced dentin-pulp complex. However, tooth germ cells and papilla cells at late bell stage generated irregular bone-dental-like structures.
In conclusion, dissociated dental epithelial and mesenchymal cells could recapitulate the embryonic tooth germ environment to favour normal tooth development, indicating that the dissociated single dental cell retained genetic signaling network which is necessary for odontogenesis.
Part 2. Differentiation of tooth germ microenvironment induced skin dermal multipotent stem cells
In present study we sought to explore the possibility of utilizing DMSCs easily available from skin tissue for odontogenic induction. Using the limiting-dilution technique, colony-forming cell population was isolated and characterized by proliferative activity and multilineage differentiation potential. By in vitro exposure to conditioned medium of embryonic and neonatal tooth germ cells in culture, the proliferation and mineralization activity of DMSCs was elevated while the embryonic tooth germ cell conditioned medium (ETGC-CM) produced more significant effects. Meanwhile, TGC-CM treated DMSCs phenocopied the odontoblasts as indicated by specific lineage markers. To further examine the in vivo development potential of induced DMSCs, TGC-CM pretreated scaffolds were loaded with treated DMSCs. Following in vivo subcutaneous transplantation, ETGC-CM treated DMSCs were capable of producing blocks of dentin-like matrix as proved by positive staining of BSP and DSP. While NTGC-CM treated DMSCs formed fewer mineral nodules inside the scaffolds which were morphologically and immunochemically identified as bone-like tissues.
These observations suggest that under the sufficiently potent inductive microenvironment, DMSCs can be directed into odontoblast-like lineage cells. Our results further posit that the extrinsic niche where cells reside in is continuously required to maintain odontogenic differentiation. More suitable and optimal odontogenic microenvironment need to be further exploited and will be of substantial utility in the context of choosing non-dental adult stem cells for tooth regeneration. Our work highlights the potential utility of DMSCs as an alternative candidate cell source in hopes of developing more practical strategy of tooth regeneration research and offering promising opportunities for therapeutic approach.
Part 3. Differentiation of tooth germ microenvironment induced gingival epithelial stem cells
In this study, we isolated and characterized gingival epithelial cell population, from which existed a subpopulation that have stem cell properties, such as colony forming ability, slow cell cycle, capacity for self-renewal, and undifferentiated state as indicated by positive staining ofβ1-Integrin and CK14. To evaluate their odontogenic differentiation potential, cap stage tooth germ development niche was chosen to establish different patterns of cell interaction including TGC-CM, ordered and mixed contact co-culture. The data accumulated here showed that the ordered contact co-culture systems can effectively induce GESCs toward the ameloblasts phenotype, while the TGC-CM and mixed contact co-culture could not effectively initiate the odontogenic differentiation of GESCs. Following in vivo transplantation as cell pellets, there was no sufficient experimental evidence showed that induced GESCs could form enamel-like tissues.
Taken together, it confirms the critical role of molecular signals in the microenvironment of cap stage tooth germ. Furthermore, the results also indicate that in order to accomplish tooth regeneration, it will be best if the natural process of epithelial–mesenchymal interactions of teeth embryonic development can be reiterated in vitro or in vivo. Accordingly, growth factors and their reservation and transmission through a substrate to anchor the candidate cells could be achieved as natural tooth initiation and morphogenesis.
引文
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