Molecular Regulation of Human Dental Stem Cell Property

人类牙干细胞特性的分子调控

• 批准号: 7493823
• 负责人: CUN-YU WANG
• 金额: $ 35.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493823
• 关键词: Attenuated; Bone Marrow; Cell Differentiation process; Cell Therapy; Cell physiology; Cells; Complex; Condition; Defect; Dental; Dental Cementum; Dental Pulp; Dental caries; Dentin; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Gelshift Analysis; Genetic Transcription; Growth Factor; Human; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Longevity; Maintenance; Mediating; Mediator of activation protein; Medicine; Mesenchymal; Mesenchymal Stem Cells; Molecular; Molecular Biology; Natural regeneration; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phosphotransferases; Population; Property; Pulpitis; Regulation; Research Personnel; Retroviridae; Signal Pathway; Signal Transduction; Site; Stem cells; Structure; Surface; TNF gene; Telomerase; Therapeutic; Time; Tissues; Western Blotting; Wnt proteins; base; clinical application; clinically relevant; human TERT protein; human adult stem cell; in vivo; multipotent cell; novel; oral pathogen; postnatal; postnatal human; programs; reconstitution; repaired; self-renewal; stem; transcription factor

The long-time objective of this application is to understand the molecular biology of human postnatal stem cells from dental and periodontal tissues. Recently, human postnatal dental pulp stem cells (DPSCs) have been identified from dental pulp tissues. These cells are multipotent and can generate dentin/pulp-like complexes in vivo. Our exciting preliminary studies presented in this application also discovered that human periodontal ligament (PDL) contains unique stem cells (periodontal ligament stem cells; PDLSCs) which can generate a distinct cementum/PDL-like structure. These human postnatal dental and periodontal stem cells offer an attractive regenerative therapy for dental and periodontal defects caused by dental decay/pulpitisand periodontitis. However, before pushing them into clinical application, it is critical to develop optimal conditions to maintain their sternness during ex vivo expansion and to elucidate molecular mechanisms which control their differentiation and self-renewal. Like bone marrow mesenchymal stem cells (MSCs), these human postnatal dental stem cells appear to be from mesenchymal origin according to their surface markers. During in vitro culture, we also found that these stem cells, similar to MSCs, progressively lost their sternness. Based on our novel findings on the maintenance of MSCs' function by telomerase, in this application, we will examine whether over-expression of telomerases help to maintain human postnatal dental stem cell properties in vitro and whether Wnt growth factors stimulate telomerase activity and modulate their properties. Moreover, our preliminary studies suggest that Wnt signaling may negatively regulate the activation of NF-icB, a master transcription factor of inflammatory responses, and that NF-KB activated by inflammatory mediators such as TNF inhibit differentiation. Therefore, in this application, we will also explore whether Wnt signaling attenuates the inhibition of human dental stem cell differentiation by TNF. In the realm of therapeutic regeneration for dental and periodontal tissues, due to infection of oral pathogens, the repairing sites are frequently inflamed. Thus, our studies are highly clinically-relevant. Collectively, novel findings from our application will provide a molecular basis for maintaining and regulating human postnatal dental stem cell properties in vitro and in vivo, and have important implications in the regenerative dental medicine.

该应用的长期目标是了解人类产后干细胞的分子生物学 来自牙齿和牙周组织的细胞。最近，人类出生后牙髓干细胞（DPSCs） 是从牙髓组织中鉴定出来的。这些细胞是多能的，可以产生牙本质/牙髓样 体内复合物。我们在本申请中提出的令人兴奋的初步研究还发现，人类 牙周膜（PDL）含有独特的干细胞（牙周膜干细胞；PDLSC），可以 产生独特的牙骨质/PDL 样结构。这些人类出生后牙齿和牙周干细胞 为由蛀牙/牙髓炎引起的牙齿和牙周缺陷提供有吸引力的再生疗法 牙周炎。然而，在将它们推向临床应用之前，开发最佳的至关重要 在离体扩增过程中保持其严格性并阐明分子机制的条件 控制它们的分化和自我更新。与骨髓间充质干细胞（MSC）一样， 根据其表面，这些人类出生后牙齿干细胞似乎来自间充质来源 标记。在体外培养过程中，我们还发现这些干细胞与间充质干细胞类似，逐渐丧失其活性。 严厉。基于我们关于端粒酶维持 MSC 功能的新发现，在本研究中 应用中，我们将检查端粒酶的过度表达是否有助于维持人类产后 牙齿干细胞的体外特性以及 Wnt 生长因子是否刺激端粒酶活性以及 调节它们的属性。此外，我们的初步研究表明 Wnt 信号传导可能会对 调节 NF-icB（炎症反应的主要转录因子）的激活，并且 NF-KB 被TNF等炎症介质激活抑制分化。因此，在这个应用程序中，我们 还将探索 Wnt 信号传导是否通过以下方式减弱对人类牙齿干细胞分化的抑制： 肿瘤坏死因子。在牙齿和牙周组织的治疗再生领域，由于口腔感染 病原体时，修复部位经常发炎。因此，我们的研究具有高度的临床相关性。 总的来说，我们应用的新发现将为维持和 在体外和体内调节人类出生后牙齿干细胞特性，并具有重要意义 在再生牙科医学中。