Regulating niche of periodontium mesenchymal stem cells under the physiological condition

生理条件下牙周间充质干细胞生态位的调节

• 批准号: 10335269
• 负责人: JIAN Q. FENG
• 金额: --
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335269
• 关键词: Ablation; Address; Adult; Apical; Apoptosis; Cells; Dental Cementum; Dental Pulp; Equilibrium; Failure; Feedback; Foundations; Future; Human; In Vitro; Investigation; LacZ Genes; Learning; Ligands; Location; Maintenance; Mesenchymal Stem Cells; Modeling; Mus; Natural regeneration; Pathologic; Pathway interactions; Periodontal Ligament; Periodontitis; Periodontium; Physiological; Plant Roots; Property; Regulation; Research; Role; Signal Transduction; Testing; Tissues; Tooth structure; Transgenic Mice; Transgenic Organisms; WNT Signaling Pathway; alveolar bone; base; design; experimental study; in vivo; injury and repair; mouse model; neurovascular; novel strategies; regenerative therapy; stem cell biomarkers; stem cell niche; stem cell population; stem cells; tissue injury; treatment strategy

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.

生理条件下牙周间充质干细胞生态位的调节 牙周组织由牙骨质、牙槽骨和牙周膜之间的牙周膜（PDL）组成。他们的 众所周知，生理更新是由干细胞群支持的1, 2。主要基于体外 方法，从人磨牙 PDL3 中分离出牙周干细胞 (PDLSC)。尽管如此，在体内 牙周干细胞的位置和鉴定仍然很大程度上未知。 尽管有各种治疗方法，但牙周炎期间或之后的牙周再生是最具挑战性的问题 正在设计的策略。再生能力的差异强烈表明牙周干细胞 在生理或病理条件下表现不同。众所周知，干细胞的活性是 受它们所居住的生态位调节。各种生态位信号相互作用，相互影响并保持干细胞 处于动态平衡4, 5。尽管其他干细胞群的利基研究取得了巨大进展， 牙周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) 并了解它们的生态位组织。根据我们的初步实验， Gli1+ 细胞被鉴定为成人牙周组织的 MSC。 Gli1+细胞完全围绕 神经血管束，并且在 PDL 空间的顶端区域更加丰富。这些 Gli1+ 细胞是 谱系分化或经典 MSC 标记呈阴性。它们产生 PDL、牙骨质、肺泡 生理周转期间的骨和根髓。经典 Wnt 信号传导的阻断会导致 Gli1+ 干细胞激活和严重的牙周组织损失。 根据这些初步发现，建议进行全面的研究以研究其体内特性 并在生理条件下调节Gli1+牙周间充质干细胞的生态位。假设 Gli1+ MSC 是牙周组织内的主要干细胞群，受负反馈调节 牙周膜内的循环。规范 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硬化素配体负向调节 Gli1+ 干细胞 活动。两个相反信号之间的相互作用使牙周膜 MSC 保持动态平衡。