Nanofiber Scaffolds for Salivary Gland Regeneration

用于唾液腺再生的纳米纤维支架

• 批准号: 10377504
• 负责人: MELINDA LARSEN
• 金额: $ 67.15万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377504
• 关键词: Address; Affect; Alpha Cell; Anti-Inflammatory Agents; Autoimmune Diseases; Back; Bone Marrow; Cells; Cessation of life; Clinical; Connective Tissue; Deposition; Disease; Disease Progression; Environment; Excision; Extracellular Matrix; Fibrosis; Functional disorder; Genetic Markers; Gland; Head and Neck Cancer; Immune response; Impairment; Inbred NOD Mice; Inflammation; Inflammatory; Injections; Injury; Knowledge; Manipulative Therapies; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Modeling; Mouse Strains; Mus; Mutation; Myofibroblast; Nanofiber Scaffold; Natural regeneration; Non obese; Organ; Outcome; Patients; Pharmacology; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Population; Porifera; Radiation; Resected; Salivary; Salivary Gland Diseases; Salivary Glands; Severities; Signal Transduction; Sjogren' s Syndrome; Source; System; Therapeutic; Tissues; Transplantation; Work; autoimmune inflammation; autoimmune pathogenesis; base; bone marrow mesenchymal stem cell; clinically relevant; defined contribution; diabetic; drug discovery; functional restoration; healing; improved; in vivo; injured; injury and repair; insight; mouse model; nanofiber; novel therapeutics; regenerative; remediation; response; response to injury; restoration; scaffold; stem cell delivery; therapeutic target; tissue regeneration; wound healing

ABSTRACT Although extracellular matrix (ECM) remodeling is a natural response to injury, excessive ECM deposition, or fibrosis, limits regeneration, is a causative factor in hundreds of diseases, and leads to 40% of all deaths worldwide. Fibrosis occurs in salivary glands (SG) of patients treated with radiation for head and neck cancers and in patients suffering from the autoimmune disease, Sjögren’s Syndrome (SS). Despite the known inhibitory effects of fibrosis on tissue regeneration, and involvement of fibrosis in disease, the mechanisms through which fibrosis develops in the salivary gland and leads to dysfunction have not been explored. The stroma of salivary glands and other organs includes tissue-resident mesenchymal stem cells (MSCs). MSCs have inherent anti-fibrotic and anti-inflammatory functions; however, in disease states tissue- resident MSCs can undergo conversion into myofibroblasts (myo-FBs) and contribute to fibrosis. Therapeutic transplantation of MSCs has been used to treat many inflammatory disorders, with the most common tissue source for therapeutic MSCs being bone marrow (BM). Injection of BM-MSCs into non-obese diabetic (NOD) mice, a commonly used mouse model for SS, showed decreased inflammation and some limited SG functional restoration; however, effects were transient and the mechanisms leading to restored function remain unknown. Therapies that manipulate endogenous or apply exogenous MSCs hold clinical promise for diseases involving fibrosis and salivary hypofunction. Mechanisms through which tissue-resident MSCs and transplanted MSCs become fibrosis-generating myo-FBs in the SG are unknown; however, in many tissues signaling by Gli1 is required. We hypothesize that tissue-resident MSCs that undergo conversion to myo-FBs leading to fibrotic connective tissue exacerbating autoimmune disease and salivary dysfunction. The objective of this proposal is to determine if modulation of tissue-resident MSCs can limit fibrosis, inflammation, and restore gland function in injured and diseased salivary glands. We will address several important clinically relevant questions in this proposal: 1) Does Gli1 signaling contribute to fibrosis in injured/diseased salivary glands? 2) Can tissue- resident myo-FBs revert to a pro-regenerative MSC state and what are the associated genetic changes that demark this conversion? 3) In a murine Sjögren’s Syndrome model, will limiting conversion of tissue-resident MSCs into myo-FBs limit fibrosis, decrease disease progression, and facilitate functional restoration? The outcomes of our proposed study are expected to improve scientific knowledge by revealing cellular mechanisms through which MSCs contribute to fibrosis in SG. These findings will have a positive impact by identifying potential therapeutic targets. In addition, we will optimize scaffold delivery systems for MSCs and anti-fibrotic pharmacologicals for reducing fibrosis and restoring function in hypofunctioning salivary glands and other organs.

摘要 尽管细胞外基质(ECM)重构是对损伤、过度ECM沉积或纤维化的自然反应， 限制再生，是数百种疾病的致病因素，并导致全世界40%的死亡。纤维化 发生在接受放射治疗的头颈部癌症患者的唾液腺(SG)和患有 自身免疫性疾病，干燥综合征(SS)。尽管已知纤维化对组织再生的抑制作用， 以及纤维化在疾病中的参与，纤维化在唾液腺中发展并导致 功能障碍还没有被研究过。涎腺和其他器官的间质包括驻留在组织中的间充质。 干细胞(MSCs)。MSCs具有固有的抗纤维化和抗炎功能；然而，在疾病状态下，组织- 驻留的MSCs可以转化为肌成纤维细胞(myo-FBS)，并有助于纤维化。治疗性的 骨髓间充质干细胞移植已被用于治疗许多炎症性疾病，最常见的组织来源是 治疗性MSCs为骨髓(BM)。将BM-MSCs注射到非肥胖糖尿病(NOD)小鼠体内，这是一种常见的 用小鼠制作SS模型，炎症减轻，SG功能恢复有限，但对 是暂时的，导致功能恢复的机制仍不清楚。操纵内源性的疗法 或者应用外源性MSCs对涉及纤维化和唾液功能减退的疾病具有临床前景。机制 组织驻留的MSCs和移植的MSCs是通过什么途径在SG内形成纤维化的Myo-FBS尚不清楚； 然而，在许多组织中，Gli1信号是必需的。我们假设，组织驻留的MSCs经历了 转化为myo-FBS导致纤维结缔组织，加重自身免疫性疾病和唾液功能障碍。 这项建议的目的是确定组织驻留的MSCs的调节是否可以限制纤维化、炎症和 恢复受伤和患病的唾液腺的腺体功能。我们将讨论几个重要的临床相关问题 这项提案中的问题：1)Gli1信号是否有助于唾液腺损伤/患病的纤维化？2)组织- 驻留的Myo-Fb恢复到促进再生的MSC状态，与此相关的基因变化是什么 转换？3)在小鼠干燥综合征模型中，是否会限制组织驻留的MSCs向myo-FBS的转换 限制纤维化，减少疾病进展，促进功能恢复？我们建议的研究结果如下 有望通过揭示骨髓间充质干细胞促进肝纤维化的细胞机制来提高科学知识 SG.这些发现将通过确定潜在的治疗靶点产生积极影响。此外，我们还将优化 骨髓间充质干细胞支架给药系统及抗肝纤维化药物的研究 唾液腺和其他器官功能减退。