Molecular Regulation of Human Dental Stem Cell Properties

人类牙干细胞特性的分子调控

• 批准号: 7895939
• 负责人: CUN-YU WANG
• 金额: $ 36.58万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895939
• 关键词: Apical; Biological Assay; Bone Marrow; Boxing; Canis familiaris; Cell physiology; Cells; Characteristics; Complex; Dental; Dental Cementum; Dental Pulp; Dentin; Development; Developmental Process; Embryo; Enzymes; Epigenetic Process; Event; Female; Gene Activation; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Screening; Genetic Transcription; Hereditary Disease; Histone H3; Histones; Human; Human Genetics; Immunodeficient Mouse; Immunoprecipitation; Implant; In Vitro; Incisor; Inherited; Link; Luciferases; Lysine; Mandible; Maxilla; Mesenchymal Stem Cells; Methylation; Modification; Molecular; Molecular Biology; Molecular Genetics; Mutation; Natural regeneration; Nature; Nodule; Ocular orbit; Odontoblasts; Osteoblasts; Patients; Pattern; Periodontal Ligament; Plant Roots; Play; Polymerase Chain Reaction; Population; Property; Public Health; Regulation; Reporter; Repression; Role; Stem cells; Structure; Syndrome; Testing; Time; Tissues; Tooth structure; Transcriptional Activation; Ubiquitination; Work; Wound Healing; base; bone; chromatin immunoprecipitation; chromatin modification; craniofacial; demethylation; forkhead protein; histone modification; human disease; improved; in vivo; inhibitor/antagonist; insight; knock-down; loss of function; male; novel; novel strategies; postnatal human; programs; promoter; public health relevance; repaired; self-renewal; small hairpin RNA; small molecule; stem cell differentiation; tissue regeneration; tongue papilla

DESCRIPTION (provided by applicant): Human postnatal dental stem cells such as dental pulp stem cells (DPSCs) and stem cells from root apical papilla (SCAPs) are unique precursor populations isolated from dental tissues based on the primary characteristics of bone marrow mesenchymal stem cells (MSCs). Like bone marrow MSCs, dental stem cells are self-renewing, multipotent, and clonogenic. They can be induced to differentiate into odontoblast- or osteoblast-like cells and form mineralized nodules in vitro. When implanted into immunodeficient mice, dental stem cells can form dentin- or cementum-like mineralized tissues or related craniofacial structures. Hence dental stem cells may present promising prospects for tooth regeneration and tissue repair. However, currently, the molecular regulation of their differentiation is poorly understood. Histone demethylases are newly-identified enzymes for removing histone methyl markers associated with gene activation or silencing. While they have been implicated in developmental processes and human diseases, it is largely unknown whether and how histone demethylases play a critical role in regulating dental stem cell differentiation. By studying oculofacialcardiodental syndrome (OFCD), a rare human genetic disorder characterized by teeth with extremely long roots (radiculomegaly), we unexpectedly discovered that the transcription co-repressor BCOR (Bcl-6 co-repressor) epigenetically regulates dental stem cell function and differentiation via histone demethylases. In this competing renewal, we hypothesize that histone epigenetic modification plays an important role in the regulation of dental stem cell function and differentiation. To test our hypothesis, we propose three specific aims. In Aim 1, we will explore whether and how BCOR epigenetically represses dental stem cell differentiation by histone modification. In Aim 2, we will determine whether and how BCOR mutation epigenetically de-represses gene transcription and thereby promotes dental stem cell differentiation. These two aims will augment our current work and further define how BCOR mutation promotes dental stem cell differentiation in a pathological condition. In Aim 3, we will explore whether and how a newly identified histone demethylase JMJD3 (JmjC domain-containing 3) promotes gene expression and controls dental stem cell differentiation in healthy conditions. By studying both normal and abnormal dental stem cells, our results may provide new insights into the molecular biology of human dental stem cells. Moreover, as demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for promoting dental and craniofacial tissue regeneration and repair. PUBLIC HEALTH RELEVANCE: Human postnatal dental stem cells are unique precursor populations which are isolated tooth. These cells are capable of differentiating into dentin/bone-like forming cells. When implanted into immunodeficient mice, dental stem cells can form dentin- or cement-like mineralized tissues. Although dental stem cells may present promising application prospects in tooth regeneration and repair, currently, molecular regulation of their fate is poorly understood. Histone demethylases are newly-identified enzymes that remove histone methyl marks associated with gene activation or repression. While they have been implicated in developmental processes and human diseases, it is largely unknown whether and how histone demethylases play a critical role in dental stem cell function. In this application, we propose to examine how chromatin modification by histone demethylases regulates gene expression and dental stem cell differentiation using molecular and genetic approaches. Our results may provide new insights into the molecular biology of human dental stem cells. Moreover, because demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for improving dental and craniofacial tissue regeneration and repair.

描述（由申请人提供）：人类出生后牙齿干细胞，如牙髓干细胞（DPSCs）和根尖乳头干细胞（SCAPs）是基于骨髓间充质干细胞（MSCs）的主要特征从牙齿组织中分离出来的独特前体细胞。与骨髓间充质干细胞一样，牙干细胞具有自我更新、多能性和克隆性。它们可以在体外诱导分化成成牙髓细胞或成骨细胞样细胞并形成矿化结节。当植入免疫缺陷小鼠体内时，牙干细胞可以形成牙本质或牙骨质样矿化组织或相关的颅面结构。因此，牙干细胞在牙齿再生和组织修复方面具有广阔的应用前景。然而，目前对其分化的分子调控机制了解甚少。组蛋白去甲基化酶是新发现的去除与基因激活或沉默相关的组蛋白甲基标记的酶。虽然它们与发育过程和人类疾病有关，但组蛋白去甲基化酶是否以及如何在调节牙齿干细胞分化中发挥关键作用在很大程度上是未知的。通过研究眼面心齿综合征（oculofacialcardiodental syndrome， OFCD），一种罕见的人类遗传疾病，其特征是牙齿具有极长的根（根肥大），我们意外地发现转录共抑制因子Bcl-6共抑制因子BCOR （Bcl-6共抑制因子）通过组蛋白去甲基化酶表观遗传调节牙齿干细胞的功能和分化。在这种竞争性更新中，我们假设组蛋白表观遗传修饰在牙干细胞功能和分化的调节中起重要作用。为了验证我们的假设，我们提出了三个具体目标。在Aim 1中，我们将探讨BCOR是否以及如何通过组蛋白修饰从表观遗传上抑制牙干细胞分化。在Aim 2中，我们将确定BCOR突变是否以及如何在表观遗传上去抑制基因转录，从而促进牙干细胞分化。这两个目标将增强我们目前的工作，并进一步确定BCOR突变如何促进牙干细胞在病理条件下的分化。在Aim 3中，我们将探索新发现的组蛋白去甲基化酶JMJD3 （JmjC结构域3）是否以及如何在健康条件下促进基因表达并控制牙干细胞分化。通过对正常和异常牙干细胞的研究，我们的结果可能为人类牙干细胞的分子生物学提供新的见解。此外，由于去甲基酶作为一种酶，可以很容易地被小分子抑制剂靶向，我们的工作可能有助于开发促进牙齿和颅面组织再生和修复的新策略。