Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption
Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption
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DOI：
10.1073/pnas.1810200115
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发表时间：
2019-01-08
影响因子：
11.1
通讯作者：
Ono, Wanida
中科院分区：
文献类型：
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作者：
Takahashi, Akira;Nagata, Mizuki;Ono, Wanida
功能性骨骼组织的形成需要间充质祖细胞分化的高度组织化步骤。发育中牙齿周围的牙囊(Df)中含有各种分化细胞的间充质祖细胞，构成牙根-骨界面，并依赖于甲状旁腺激素相关肽(PTHrP)和PTH/PTHrP受体(PPR)的信号来协调牙齿萌出。然而，DF中间充质前体细胞的身份以及它们如何受到PTHrP-PPR信号的调控仍不清楚。在这里，我们发现PTHrP-PPR自分泌信号维持着DF间充质祖细胞的生理细胞命运，从而建立起功能性的牙周附着装置，并协调牙齿萌出。单细胞RNA-seq分析显示PTHrP(+)细胞具有细胞异质性，其中PTHrP(+)DF亚群大量表达PPR。使用他莫昔芬诱导的PTHrP-Creer小鼠进行的细胞谱系分析表明，在牙根形成过程中，PTHrP(+)DF细胞在无细胞牙骨质、牙周膜细胞和牙槽隐骨成骨细胞上分化为成牙骨质细胞。PPR缺失导致PTHrP(+)DF间充质祖细胞向非生理性成牙骨质样细胞转移，在牙根表面早熟形成细胞牙骨质，并伴随着MEF2C和基质蛋白的上调，导致牙周附着装置丧失和牙萌出的原发失败，这与PPR突变引起的人类遗传条件非常相似。这些发现揭示了一种独特的机制，即由PTHrP-PPR信号介导的自分泌系统紧密地维持间充质前体细胞的适当细胞命运，以实现骨骼组织的功能性形成。
Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root-bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular hetero-geneity of PTHrP(+) cells, wherein PTHrP(+) DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP(+) DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP(+) DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.