Postnatal Stem Cell-Mediated Tooth Regeneration

描述(申请人提供)：本申请的目的是进一步鉴定新发现的来源于根尖乳头(SCAP)的干细胞，并探索在小型猪模型中使用SCAP和牙周膜干细胞(PDLSCs)通过常规的临床种植程序在无牙区再生牙根/牙周组织的潜力。我们最近分离了人的SCAP，并发现它们与其他牙科干细胞如牙髓干细胞(DPSCs)有不同的特性。特别是，SCAP显示了体内牙本质再生能力的增强，独特的基因表达谱，以及可检测到的端粒酶活性水平。我们的初步研究表明，SCAP是负责生根的早期干祖细胞，这表明SCAP可能在牙科组织再生中具有优势。在SCAP被考虑用于任何临床应用之前，深入了解其干细胞特性是至关重要的。最近，我们发表了部分初步数据，证明自体SCAP和PDLSCs能够在新拔除的牙齿窝内生成牙根/牙周膜组织，作为小型猪瓷冠安装的支撑物。然而，这种早期的“原则证明”证据并不代表常规的临床植入程序。因此，我们建议探索利用SCAP和PDLSCs在无牙区再生牙根/牙周组织的潜力，以模拟临床种植治疗。这一方法可能为未来潜在的临床应用提供关键证据。 在这项应用中，我们将表征人和小型猪SCAP的多潜能分化，然后利用小型猪SCAP和PDLSCs，一种能够形成牙周组织的干细胞群体，合作再生牙根/PDL复合体。之所以选择小型猪进行牙根/牙周组织再生，是因为它们在口面部组织结构和牙齿干细胞特性方面与人类相似。我们将使用分子、细胞、组织学、免疫学和干细胞移植方法来鉴定人类SCAP和小型猪SCAP/PDLSCs。这项拟议的研究的最终目标是探索在临床前模型中利用两种牙科干细胞群体重建生物牙根/牙周复合体的潜力。我们预计，我们在这一R21应用中提出的研究将导致未来R01的应用。

DESCRIPTION (provided by applicant): The objective of this application is to further characterize newly identified Stem Cells derived from root Apical Papilla (SCAP) and explore the potentiality of using SCAP along with periodontal ligament stem cells (PDLSCs) to regenerate root/periodontal tissue in the edentulous region by regular clinical dental implant procedures in a minipig model. We have recently isolated human SCAP and found their distinct properties from other dental stem cells such as dental pulp stem cells (DPSCs). In particular, SCAP show an increased dentin regeneration capacity in vivo, a distinct gene expression profile, and detectable levels of telomerase activity. Our preliminary studies imply that SCAP are early stem progenitors responsible for root formation, suggesting that SCAP may have advantages to be utilized for dental tissue regeneration. Before SCAP are considered for any clinical application, it is critical to understand their stem cell properties in depth. Very recently, we published part of our preliminary data to demonstrate that autologous SCAP and PDLSCs are capable of generating root/periodontal ligament tissues in the socket of newly extracted tooth to serve as a supporter to install porcelain crown in minipigs. However, this early "proof of principle" evidence does not represent regular clinical implant procedures. Therefore, we propose to explore potential of using SCAP and PDLSCs to regenerate root/periodontal tissues in the edentulous region mimicking clinical dental implant therapies. This approach may provide critical evidence for potential clinical application in the future. In this application, we will characterize multipotent differentiation of human and minipig SCAP and then utilize minipig SCAP and PDLSCs, a stem cell population capable of forming periodontal tissue, to cooperatively regenerate root/PDL complex. The reason of selecting minipigs for root/periodontal tissue regeneration is due to their similarity to humans in terms of their orofacial tissue structures and characteristics of dental stem cells. We will use molecular, cellular, histological, immunological, and stem cell transplantation approaches to characterize human SCAP and minipig SCAP/PDLSCs. The final goal of this proposed study is to explore potential of utilizing two populations of dental stem cells to reconstruct biologic root/periodontal complex in a pre-clinical model. We anticipate that our proposed studies in this R21 application will lead to a R01 application in the future.