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: 9973250
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973250
• 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 Therapy; Cell physiology; Cells; Cellular Morphology; Characteristics; Clinical Management; Cultured Cells; Defense Mechanisms; Development; Diabetes Mellitus; Differentiation Antigens; Disease; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Ethical Issues; Exhibits; Experimental Models; Extracellular Matrix; Extracellular Matrix Proteins; Fibroins; Film; Functional disorder; Growth; Head Cancer; Health; Lead; Legal patent; Mesenchymal Stem Cells; Monitor; Morphology; Mouth Diseases; Multipotent Stem Cells; Natural regeneration; Neck Cancer; 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; Technology; Testing; Time; Tissue Engineering; Tissues; Xerostomia; base; clinically relevant; design; embryonic stem cell; engineered stem cells; experimental study; human stem cells; in vivo; in vivo Model; induced pluripotent stem cell; innovation; irradiation; multidisciplinary; novel; novel therapeutic intervention; physical property; preservation; progenitor; regenerative; regenerative therapy; repaired; scaffold; stem; stem cell differentiation; stem cell niche; stem cell proliferation; stem cells; 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.

项目概要 唾液是保护口腔健康的重要防御机制。唾液腺 (SG) 功能减退 导致不受控制的严重口腔疾病，从而严重影响生活质量。 SG 高度分化，一旦被治疗或破坏，几乎没有再生能力 疾病（例如放射治疗或自身免疫性干燥综合征）。因此，发展 保存或再生 SG 分泌功能的策略对于成功至关重要 对这些患者的管理。细胞外基质（ECM）是独特的细胞外基质的主要组成部分。 指导和维持体内细胞分化功能的微环境或“生态位” 目前，基于干细胞的再生疗法存在两个主要障碍：1）有限。 多能干细胞的可用性和2）选择性控制分化的难度 多能干细胞转化为所需的细胞谱系。我们的研究小组开发了一种新型 ECM- 用于从骨中扩增多能间充质干细胞 (MSC) 的细胞培养系统 骨髓和 3D 丝素蛋白支架 (SFS)，用于离体建立 SG 生态位。因此，我们 提议测试建立在自然 3D 基础上的唾液腺特异性 ECM (SG-ECM) 的假设 SFS，是一种仿生生态位，能够指导 MSC 增殖和分化为功能性 SG 祖细胞。在具体目标 1 中，我们将优化 SG-生产的支架特性 SFS 上的 ECM 由原代 SG 上皮细胞进行。在具体目标 2 中，我们将确定是否 最佳 SG-ECM 包被的 SFS 可引导 MSC 分化为 SG 细胞谱系。在具体目标 3 中， 将在 SG 损伤的体内模型中评估在 Specific Aim 2 中产生的细胞的功效 由于辐射。 该提案的新颖之处包括（1）测试我们的新型细胞培养技术以获得足够的 来自人类骨髓的多能 MSC 数量，用于修复或再生 SG 功能； (2)测试 天然 3D 支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分化中的作用 SG细胞谱系和功能性SG单位，以及（4）组建一个多学科团队进行研究 基于干细胞的 SG 疗法。这项研究的成功可能会带来新的治疗策略 SG 功能障碍的临床管理。