[The pattern and regulatory mechanism of mammalian diphyodont tooth replacement].

Although the dental lamina of permanent teeth in human being has been developed as early as the embryo stage, the replacement of the deciduous teeth by permanent teeth does not take place untill the age of 6 to 12 years old. The molecular mechanism of the initiation of permanent teeth is still unclear. The rodent species are usually used for the tooth development research in the past. However, this animal model is not suitable for the tooth replacement study because of the absence of tooth replacement in rodents. After 10 years of efforts, our team has established the animal model of miniature pig for tooth replacement research. Using this model, we firstly defined the spatiotemporal pattern of teeth replacement. In the further mechanism research, results showed that the growing rate of the deciduous teeth was faster than that of the surrounding alveolar bone, and biomechanical stress inside mandible was generated due to the fast growth of deciduous teeth. The stress might up-regulate the signal of Runt-related transcription factor 2 (RUNX2)-Wnt pathway in the mesenchyme between the deciduous and permanent teeth, sustain the successional dental lamina at the resting stage and inhibit the development of permanent teeth. A similar expression pattern was also found in the mesenchyme between the deciduous and permanent teeth in human. Our findings demonstrated that the eruption of deciduous tooth released the stress inside mandible, thus induced the "Wnt translocation" from the mesenchyme into the epithelium of permanent counterpart and therefore initiated the development of permanent teeth. The underlying mechanism of the replacement of deciduous teeth by permanent teeth is the regulation of biomechanical stress throughout the initiation process. Based on the findings, we proposed the theory of "biomechanical stress regulation of the tooth replacement" . The replacement pattern and regulatory mechanism provide a scientific foundation for the organ development and regeneration by regulating the biomechanical stress and Wnt pathway in the future.尽管人类替换恒牙的牙板在胚胎时就已经形成，但直到6~12岁期间才进行乳恒牙替换，这种替换恒牙时空启动的调控分子机制一直不清楚。因以往牙发育研究多以啮齿类动物为研究模型，没有乳恒牙替换，无法进行人类乳恒牙替换相关研究。本课题组经过10余年努力，创建小型猪牙发育研究平台，利用此大型动物模型开展乳恒牙发育替换模式和机制研究。明确了小型猪乳恒牙替换的时空发育模式，进一步的牙替换机制研究表明，乳牙发育速率快于颌骨产生的组织内生物应力；该应力上调乳恒牙之间间充质内Runt相关转录因子2（Runt-related transcription factor 2，RUNX2）-Wnt信号，抑制替换恒牙牙板发育，使替换恒牙牙板较长时间处于相对静止状态；该分子表达模式在人乳恒牙牙胚之间间充质内得到验证；乳牙萌出释放组织内应力引起Wnt信号从间充质转位至恒牙上皮启动恒牙发育。由此发现了组织内应力调控乳恒牙替换的机制，提出"组织内应力调控牙齿替换"学说。乳恒牙替换模式及调控机制的发现为通过调控生物力学及Wnt通路实现器官发育与再生提供了科学基础。.