Molecular Regulation of Human Dental Stem Cell Property

人类牙干细胞特性的分子调控

• 批准号: 7053372
• 负责人: CUN-YU WANG
• 金额: $ 36.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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/7053372
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; cell differentiation; cell growth regulation; cementum; dental caries; dental pulp; dental structure; enzyme activity; gel mobility shift assay; growth factor; hematopoietic tissue transplantation; human tissue; laboratory mouse; molecular biology; northern blottings; nuclear factor kappa beta; periodontitis; periodontium disorder; polymerase chain reaction; regeneration; stem cell transplantation; telomerase; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): 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/pulpitis and 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-kappaB, a master transcription factor of inflammatory responses, and that NF-kappaB 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.

描述（由申请人提供）：本申请的长期目标是了解来自牙齿和牙周组织的人类产后干细胞的分子生物学。最近，从牙髓组织中鉴定出了人类出生后牙髓干细胞（DPSC）。这些细胞是多能的，可以在体内产生牙本质/牙髓样复合物。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/牙髓炎和牙周炎引起的牙齿和牙周缺陷提供了有吸引力的再生疗法。然而，在将它们推向临床应用之前，至关重要的是开发最佳条件以在离体扩增过程中保持其严格性，并阐明控制其分化和自我更新的分子机制。与骨髓间充质干细胞 (MSC) 一样，这些人类出生后牙齿干细胞根据其表面标记似乎来自间充质来源。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，逐渐失去了它们的干性。基于我们关于端粒酶维持间充质干细胞功能的新发现，在本申请中，我们将研究端粒酶的过度表达是否有助于在体外维持人出生后牙干细胞的特性，以及Wnt生长因子是否刺激端粒酶活性并调节其活性。特性。此外，我们的初步研究表明，Wnt 信号传导可能负向调节 NF-kappaB（炎症反应的主要转录因子）的激活，并且 TNF 等炎症介质激活的 NF-kappaB 会抑制分化。因此，在本申请中，我们还将探讨Wnt信号传导是否减弱TNF对人牙干细胞分化的抑制。在牙齿和牙周组织的治疗再生领域，由于口腔病原体的感染，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在体外和体内维持和调节人类出生后牙科干细胞特性提供分子基础，并对再生牙科医学具有重要意义。