Molecular Regulation of Human Dental Stem Cell Properties

人类牙干细胞特性的分子调控

• 批准号: 8640912
• 负责人: CUN-YU WANG
• 金额: $ 36.21万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640912
• 关键词: Apical; Biological Assay; Bone Marrow; Boxing; Canis familiaris; Cell Differentiation process; 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; Regulation; Reporter; Role; Stem cells; Structure; Syndrome; Testing; Time; Tissues; Tooth structure; Transcriptional Activation; Ubiquitination; Work; base; bone; chromatin immunoprecipitation; chromatin modification; craniofacial; demethylation; forkhead protein; gene repression; 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; tissue repair; 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.

描述（由申请人提供）：人出生后牙干细胞，如牙髓干细胞（DPSC）和根尖乳头干细胞（SCAP）是基于骨髓间充质干细胞的主要特征从牙组织中分离出来的独特前体细胞群（间充质干细胞）。与骨髓间充质干细胞一样，牙科干细胞具有自我更新、多能性和克隆性。它们可以被诱导分化成成牙本质细胞或成骨细胞样细胞，并在体外形成矿化结节。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颅面结构。因此，牙干细胞可能为牙齿再生和组织修复带来广阔的前景。然而，目前对其分化的分子调控知之甚少。组蛋白去甲基酶是新发现的酶，用于去除与基因激活或沉默相关的组蛋白甲基标记。虽然组蛋白去甲基酶与发育过程和人类疾病有关，但目前尚不清楚组蛋白去甲基酶是否以及如何在调节牙齿干细胞分化中发挥关键作用。通过研究眼面心齿综合征（OFCD）这种罕见的人类遗传性疾病，其特征是牙齿根极长（牙根肥大），我们意外地发现转录辅阻遏物BCOR（Bcl-6辅阻遏物）在表观遗传上调节牙齿干细胞的功能和分化通过组蛋白去甲基化酶。在这种竞争更新中，我们假设组蛋白表观遗传修饰在牙齿干细胞功能和分化的调节中发挥重要作用。为了检验我们的假设，我们提出了三个具体目标。在目标 1 中，我们将探讨 BCOR 是否以及如何通过组蛋白修饰在表观遗传上抑制牙齿干细胞分化。在目标 2 中，我们将确定 BCOR 突变是否以及如何在表观遗传上抑制基因转录，从而促进牙齿干细胞分化。这两个目标将增强我们当前的工作，并进一步明确 BCOR 突变如何促进病理条件下的牙齿干细胞分化。在目标 3 中，我们将探讨新鉴定的组蛋白去甲基化酶 JMJD3（含 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齿干细胞分化。通过研究正常和异常的牙齿干细胞，我们的结果可能为人类牙齿干细胞的分子生物学提供新的见解。此外，由于去甲基酶作为酶，很容易被小分子抑制剂靶向，因此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。