Regulating niche of periodontium mesenchymal stem cells under the physiological condition

生理条件下牙周组织间充质干细胞的生态位调控 牙周组织由牙骨质、牙槽骨和介于两者之间的牙周膜组成。他们的 已知生理周转是由干细胞群支持的1，2。主要基于体外 方法：从人磨牙牙周膜3中分离牙周膜干细胞。尽管如此，在体内 牙周组织干细胞的定位和鉴定仍然是未知的。 牙周炎期间或之后的牙周再生是最具挑战性的问题，尽管有各种治疗方法 正在设计的战略。再生能力的差异强烈表明牙周组织干细胞 在生理或病理条件下表现不同。已知干细胞的活性 由他们居住的生态位来管理。各种小生境信号相互作用，使干细胞 在一个动态平衡4，5.尽管对其他干细胞群体的生态位研究取得了巨大进展， 牙周组织干细胞的体内生态位从未被研究过。 为了应对上述挑战，必须找出牙周组织的体内特性 间充质干细胞（MSC）和学习他们的生态位组织。基于我们的初步实验， Gli1+细胞被鉴定为成人牙周组织的间充质干细胞。Gli1+细胞只围绕着 神经血管束，并在PDL间隙的顶端区域更丰富。这些Gli1+细胞 对于谱系分化或经典MSC标志物为阴性。它们产生牙周膜、牙骨质、牙槽骨 骨和根尖髓在生理周转。经典Wnt信号传导的阻断导致 Gli1+干细胞活化与严重牙周组织缺损 有了这些初步的研究结果，提出了全面的调查，调查在体内的性质 以及在生理条件下调控Gli1+牙周组织MSCs的生态位。假设Gli1+ 骨髓间充质干细胞是牙周组织中的主要干细胞群，受负反馈调节 牙周组织内的环。典型的Wnt信号通路激活并维持牙周组织MSC。 牙骨质和牙槽骨分泌的Sclerostin配体对Gli1+干细胞的负调控作用 活动这两种相反的信号之间的相互作用使牙周组织MSC保持动态平衡。

Regulating niche of periodontium mesenchymal stem cells under the physiological condition The periodontium is composed of cementum, alveolar bone and periodontal ligament (PDL) in between. Their physiological turnover was known to be supported by stem cell populations1, 2. Based on mostly in vitro approaches, the periodontal stem cells (PDLSC) were isolated from human molar PDL3. Despite of that, in vivo location and identification of the periodontium stem cells remain largely unknown. Periodontium regeneration during or after periodontitis is a most challenging issue despite of various treatment strategies being designed. The regeneration capability difference strongly suggests that periodontium stem cells behave differentially under physiological or pathological conditions. Activity of stem cells was known to be regulated by the niche they are residing in. Various niche signals interplay which each other and keep stem cells in a dynamic balance4, 5. Despite of tremendous progress of the niche studies for other stem cell populations, the in vivo niche of periodontium stem cells has never been studied. To address above challenges, it is therefore imperative to find out the in vivo identity of the periodontium mesenchymal stem cells (MSCs) and to learn their niche organization. Based on our preliminary experiments, Gli1+ cells are identified as the MSCs for adult periodontium tissue. The Gli1+ cells are exclusively surrounding the neurovascular bundle and are more enriched in the apical region of the PDL space. These Gli1+ cells are negative for lineage differentiation or classical MSC markers. They give rise to the PDL, cementum, alveolar bone and apical root pulp during physiological turnover. Blockage of canonical Wnt signaling leads to failure of Gli1+ stem cells activation and severe periodontal tissue loss. With these preliminary findings, comprehensive investigation is proposed for investigating the in vivo properties and regulating niche of Gli1+ periodontium MSCs under physiological condition. The hypothesis is that Gli1+ MSCs are the dominant stem cell population within the periodontium and are regulated by a negative feedback loop within the periodontium. Canonical Wnt signaling pathway activates and maintains periodontium MSCs. Sclerostin ligand secreted from the cementum and alveolar bone negatively regulates the Gli1+ stem cell activities. Interplays between the two opposing signals keep the periodontium MSCs in a dynamic balance.