Postnatal Stem Cell-Mediated Tooth Regeneration

描述（由申请人提供）：本申请的目的是进一步表征新发现的来自根尖乳头（SCAP）的干细胞，并在小型猪模型中通过常规临床牙种植程序探索使用SCAP和牙周韧带干细胞（PDLSCs）在无牙区域再生根/牙周组织的潜力。我们最近分离了人类SCAP，并发现它们与其他牙科干细胞（如牙髓干细胞）具有不同的特性。特别是，SCAP在体内表现出增加的牙本质再生能力，独特的基因表达谱和可检测的端粒酶活性水平。我们的初步研究表明，SCAP是负责根形成的早期干祖细胞，这表明SCAP在牙组织再生中可能具有优势。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能够在迷你猪新拔牙的牙槽中产生根/牙周韧带组织，作为安装瓷冠的支撑体。然而，这种早期的“原理证明”证据并不代表常规的临床植入程序。因此，我们建议利用SCAP和PDLSCs模拟临床种植牙治疗，探索无牙区根/牙周组织再生的潜力。该方法可能为未来潜在的临床应用提供关键证据。

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.