Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration.
Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration.
复制标题
DOI：
10.1016/j.biomaterials.2015.06.004
复制
发表时间：
2015-09
期刊：
影响因子：
14
通讯作者：
Mao JJ
中科院分区：
文献类型：
--
作者：
Zhou C;Yang G;Chen M;Wang C;He L;Xiang L;Chen D;Ling J;Mao JJ
LIM Homeobox 8(LHX8)是一种高度保守的转录因子，最近被证实在胆碱能和GABA能分化中发挥作用，并在发育过程中表达于神经脊来源的颅面组织。然而，Lhx8的功能和信号通路在很大程度上难以捉摸。在这里，我们发现Lhx8通过Wnt和转化生长因子β途径调节牙间充质的分化和功能。Lhx8仅在E11.5的牙间充质中表达，在E14.5达到高峰，在牙上皮中不表达。通过重组E16.5牙齿器官中的牙齿上皮和间充质，Lhx8基因敲除加速了牙齿间充质的分化；相反，Lhx8过表达减弱了牙本质的形成。Lhx8在β-磷酸三钙立方体中过表达成人牙髓干/祖细胞，抑制体内矿化基质的产生。基因图谱显示，出生后牙髓干/祖细胞在Lhx8过表达后改变了几个基质相关基因的表达，包括Dspp、Cola1和骨钙素。Lhx8转录激活Wnt和转化生长因子β途径，其抑制作用上调多个牙本质形成基因。总之，Lhx8通过微调Wnt和转化生长因子β信号来调节牙本质的发育和再生。
LIM homeobox 8 (Lhx8) is a highly conserved transcriptional factor with recently illustrated roles in cholinergic and GABAergic differentiation, and is expressed in neural crest derived craniofacial tissues during development. However, Lhx8 functions and signaling pathways are largely elusive. Here we showed that Lhx8 regulates dental mesenchyme differentiation and function via Wnt and TGFβ pathways. Lhx8 expression was restricted to dental mesenchyme from E11.5 to a peak at E14.5, and absent in dental epithelium. By reconstituting dental epithelium and mesenchyme in an E16.5 tooth organ, Lhx8 knockdown accelerated dental mesenchyme differentiation; conversely, Lhx8 overexpression attenuated dentin formation. Lhx8 overexpressed adult human dental pulp stem/progenitor cells in β-tricalcium phosphate cubes attenuated mineralized matrix production in vivo. Gene profiling revealed that postnatal dental pulp stem/progenitor cells upon Lhx8 overexpression modified several matrix related gene expression including Dspp, Cola1 and osteocalcin. Lhx8 transcriptionally activates Wnt and TGFβ pathways, and its attenuation upregulates multiple dentinogenesis genes. Together, Lhx8 regulates dentin development and regeneration by fine-turning Wnt and TGFβ signaling.