Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [CL stage]

Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=3 WT and KO (each sample contain dissected dental tissues from 3 mice combined)细胞命运由特定的转录程序所决定。本研究证实，转录共激活因子中介体1（MED1）在决定外胚层上皮的细胞命运过程中发挥关键作用。MED1敲除会破坏牙釉质形成，并导致门齿旁异位生长毛发。MED1缺失会改变牙上皮的分化方向，使其表达与皮肤类似的表皮及毛发相关基因。这种从牙谱系向表皮/毛发谱系的细胞转换，以驻留于颈环的MED1缺陷型牙上皮干细胞（dental epithelial stem cells）出现异常为特征。MED1缺陷会导致牙上皮干细胞无法完成由Notch信号通路调控的牙中间层细胞分化。反之，MED1缺陷细胞会保留干细胞特性并表达Sox2。这些细胞最终可能通过原本用于牙釉质形成的毛细血管网络提供的钙离子，获得表皮细胞命运。本研究结果表明，MED1通过调控Sox2/Notch1通路，决定牙上皮的细胞谱系分化。本研究同时证实，可利用皮肤外的基因工程改造牙组织或细胞实现毛发再生。实验设置3例野生型（WT）及3例敲除型（KO）样本，每个样本由3只小鼠的解剖获取的牙组织混合制备而成。