Zhang Ziwei, Hu Hong, Xu Zhiheng, Shan Ce, Chen Hanyi, Xie Kun, Wang Kun, Wang Yifu, Zhu Qing, Yin Yike, Cai Haoyang, Zhang Yunqiu, Li Zhonghan
Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, 24 South Section 1, 1st Ring Road, Chengdu, 610065, China.
Department of Anesthesiology, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, China.
Adv Sci (Weinh). 2025 Jan;12(3):e2404345. doi: 10.1002/advs.202404345. Epub 2024 Nov 27.
It is known for decades that dental epithelium and mesenchyme can reconstitute and regenerate a functional tooth. However, the mechanism of tooth reconstitution remains largely unknown due to the lack of an efficient in vitro model. Here, a chemically defined culture system is established that supports tooth reconstitution, further development with normal anatomy, and prompt response to chemical interference in key developmental signaling pathways, termed as toothoids. By using such a system, it is discovered that, during reconstitution, instead of resetting the developmental clock, dental cells reorganized and restarted from the respective developmental stage where they are originally isolated. Moreover, co-stimulation of Activin A and Hedgehog/Smoothened agonist (SAG) sustained the initial induction of tooth fate from the first branchial arch, which would be otherwise quickly lost in culture. Furthermore, activation of Bone Morphogenetic Protein (BMP) signaling triggered efficient enamel formation in the late-stage toothoids, without affecting the normal development of ameloblasts. Together, these data highlight the toothoid culture as a powerful tool to dissect the molecular mechanisms of tooth reconstitution and regeneration.
几十年来，人们都知道牙上皮和间充质能够重构并再生出一颗功能性牙齿。然而，由于缺乏有效的体外模型，牙齿重构的机制在很大程度上仍不为人知。在此，我们建立了一种化学成分明确的培养系统，该系统支持牙齿重构、具有正常解剖结构的进一步发育以及对关键发育信号通路中化学干扰的快速响应，我们将其称为类牙结构。通过使用这样一个系统，我们发现，在重构过程中，牙细胞并非重置发育时钟，而是从它们最初分离时的各自发育阶段进行重组并重新开始。此外，激活素A和刺猬信号通路/ smoothened激动剂（SAG）的共同刺激维持了来自第一鳃弓的牙齿命运的初始诱导，否则这种诱导在培养中会很快丧失。此外，骨形态发生蛋白（BMP）信号的激活在晚期类牙结构中触发了有效的釉质形成，而不影响成釉细胞的正常发育。总之，这些数据突出了类牙结构培养作为剖析牙齿重构和再生分子机制的有力工具。
