Recapitulation of the salivary gland niche ex vivo for stem cell-based therpies

基于干细胞疗法的离体唾液腺生态位的概括

• 批准号: 9766107
• 负责人: XIAO-DONG CHEN
• 金额: $ 37.74万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766107
• 关键词: 3-Dimensional; Acinar Cell; Aging; Area; Autoimmune Process; Basement membrane; Biochemical; Biocompatible Materials; Biological Markers; Biological Models; Biomimetics; Bone Marrow; Bone Marrow Stem Cell; Cell Culture System; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Cellular Morphology; Characteristics; Clinical Management; Cultured Cells; Defense Mechanisms; Development; Diabetes Mellitus; Differentiation Antigens; Disease; Engineering; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Ethical Issues; Exhibits; Experimental Models; Extracellular Matrix; Extracellular Matrix Proteins; Fibroins; Film; Functional disorder; Growth; Head and Neck Cancer; Health; Lead; Legal patent; Mesenchymal Stem Cells; Monitor; Morphology; Mouth Diseases; Multipotent Stem Cells; Natural regeneration; Oral health; Pathologic; Pathway interactions; Patients; Pluripotent Stem Cells; Porosity; Production; Property; Quality of life; Radiation induced damage; Radiation therapy; Rattus; Regenerative Medicine; Research; Resources; Role; Saliva; Salivary Gland Diseases; Salivary Glands; Silk; Sjogren' s Syndrome; Source; Stem cell transplant; Stem cells; Technology; Testing; Time; Tissue Engineering; Tissues; Xerostomia; base; clinically relevant; design; embryonic stem cell; experimental study; human stem cells; in vivo; in vivo Model; induced pluripotent stem cell; innovation; irradiation; multidisciplinary; novel; novel therapeutic intervention; off-patent; physical property; preservation; progenitor; regenerative; regenerative therapy; repaired; scaffold; stem; stem cell differentiation; stem cell niche; success; transdifferentiation

Project Summary Saliva is an important defense mechanism for protecting oral health. Salivary gland (SG) hypofunction results in uncontrolled and severe oral diseases that lead to severely compromised quality of life. SGs are highly differentiated and have little regenerative capacity once they are destroyed by therapy or disease (e.g. radiation therapy or autoimmune Sjögren’s syndrome). Therefore, the development of strategies for preserving or regenerating the secretory function of SGs is essential for successful management of these patients. The extracellular matrix (ECM) is a major component of the unique microenvironment or “niche” that directs and maintains the differentiated functions of cells in vivo Presently, there are two main obstacles to stem cell-based regenerative therapies: 1) the limited availability of multi-potent stem cells and 2) the difficulty of selectively controlling the differentiation multi-potent stem cells into the desired cell lineage. Our research group has developed a novel ECM- based cell culture system for expanding multipotent mesenchymal stem cells (MSCs) from bone marrow and 3D silk fibroin scaffolds (SFS) for establishing the SG niche ex vivo. Therefore, we propose to test the hypothesis that salivary gland specific ECM (SG-ECM), established on a natural 3D SFS, is a biomimetic niche capable of directing MSC proliferation and differentiation into functional SG progenitor cells. In Specific Aim 1, we will optimize scaffold characteristics for the production of SG- ECM on the SFS by primary SG epithelial cells. In Specific Aim 2, we will determine whether the optimal SG-ECM coated SFS directs MSC differentiation into the SG cell lineage. In Specific Aim 3, the efficacy of the cells, produced in Specific Aim 2, will be evaluated in an in vivo model of SG damage due to irradiation. The novelty of this proposal includes (1) testing our novel cell culture technology to obtain sufficient numbers of multipotent MSCs from human bone marrow to repair or regenerate SG function; (2) testing a natural 3D scaffold material and optimizing its properties for supporting SG regeneration and tissue engineering; (3) examining the role of SG-derived ECM coated scaffolds in directing MSC differentiation to the SG cell lineage and functional SG units, and (4) assembling a multidisciplinary team to study stem-cell based SG therapy. The success of this study may lead to new therapeutic strategies for clinical management of SG dysfunction.

项目摘要 唾液是保护口腔健康的重要防御机制。唾液是保护口腔健康的重要防御机制。唾液（SG）功能障碍 导致不受控制和严重的口腔疾病导致严重损害的生活质量。 SGS 高度差异化，一旦被治疗销毁或 疾病（例如放射疗法或自身免疫性Sjögren综合征）。因此，发展 保存或再生SG的秘密功能的策略对于成功是必不可少的 这些患者的管理。细胞外基质（ECM）是独特的主要组成部分 微环境或“利基”指导和维持体内细胞的分化功能 目前，基于干细胞的再生疗法有两个主要障碍：1）有限 多功能干细胞的可用性和2）选择性控制分化的难度 多功能干细胞进入所需的细胞谱系。我们的研究小组开发了一种新颖的ECM- 基于骨骼扩展多能间充质干细胞（MSC）的基于细胞培养系统 骨髓和3D真丝纤维蛋白支架（SFS），用于建立SG sg nike ex vivo。因此，我们 提出测试假设的假设，即在天然3D上建立的唾液腺特异性ECM（SG-ECM） SFS，是一种能够将MSC增殖和分化为功能性SG的仿生生位 祖细胞。在特定目标1中，我们将优化用于生产SG-的脚手架特征 原代SG上皮细胞在SFS上的ECM。在特定目标2中，我们将确定是否 最佳SG-ECM涂层SFS将MSC分化引导到SG细胞谱系中。在特定的目标3中 特定AIM 2中产生的细胞的功效将在SG损伤的体内模型中进行评估 由于辐照。 该提案的新颖性包括（1）测试我们的新细胞培养技术以获得足够的 从人骨髓到修复或再生SG功能的多能MSC数量； （2）测试 天然的3D脚手架材料，并优化其特性以支持SG再生和组织 工程; （3）检查SG衍生的ECM涂层支架在指导MSC差异化中的作用 到SG细胞谱系和功能性SG单元，以及（4）组装多学科团队来学习 基于干细胞的SG疗法。这项研究的成功可能会导致新的治疗策略 SG功能障碍的临床管理。