GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION

牙龈源性间充质干细胞：在免疫调节和组织再生中的作用

• 批准号: 8271275
• 负责人: Anh D Le
• 金额: $ 1.76万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271275
• 关键词: Address; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biological; Bone Diseases; Bone Marrow; Bone necrosis; Cell physiology; Cells; Cicatrix; Clinical; Clinical Data; Debridement; Defect; Dioxygenases; Disease; Disease model; Engraftment; Exhibits; Family suidae; Gingiva; Goals; Human; IL17 gene; IL6 gene; Immune; Immunocompromised Host; Immunology; Immunomodulators; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Interleukin-10; Interleukin-17; Interleukin-6; Jaw; Knowledge; Mandible; Mediating; Mesenchymal Stem Cells; Modeling; Molecular; Mouth Diseases; Mucosal Immunity; Mus; Natural regeneration; Necrosis; Nitric Oxide; Operative Surgical Procedures; Oral; Oral cavity; Oral mucous membrane structure; Pathway interactions; Periodontal Ligament; Play; Property; Regenerative Medicine; Regulatory T-Lymphocyte; Role; Secondary to; Skin; Source; Stem Cell Research; Stem cell transplant; Stem cells; T-Lymphocyte; Testing; Therapeutic; Tissues; Tooth Socket; Tumor Necrosis Factor Ligand Superfamily Member 6; abstracting; autocrine; base; bisphosphonate; bone; chemokine; craniofacial; cytokine; graft vs host disease; immune function; immunoregulation; in vivo; indoleamine; injured; injury and repair; knock-down; medical specialties; mouse model; novel; novel therapeutic intervention; oral tissue; orofacial; paracrine; pre-clinical; prevent; reconstruction; regenerative; repaired; restoration; self-renewal; stem cell biology; stem cell population; tissue regeneration; tissue repair

PROJECT SUMMARY/ABSTRACT A major roadblock in regenerative medicine is the ability to resolve disease-associated inflammation and to optimize tissue regenerative capacity to prevent further tissue destruction secondary to inflammation or scarring. Recently, a major breakthrough in mesenchymal stem cells (MSCs) research identifies an intrinsic role of MSCs in immune-regulatory function. We have demonstrated that pro-inflammatory cytokines are required for immunosuppressive function of MSCs through the concerted action of chemokines, and nitric oxide, and that activated T cells can induce apoptosis of MSCs via the Fas/Fas L pathway. Our studies also have revealed that the immunosuppressive property of skin derived MSCs were tightly regulated by the local inflammatory niche mediated by the autocrine/paracrine IL17/IL6 axis, and therapeutic approaches targeting these distinct niche components resulted in suppression of excessive scar formation. Based on these observations, we explore the feasibility of isolating MSCs from human gingiva (hGMSCs), a unique oral tissue that functions both as a biological mucosal barrier and a component of the oral mucosal immunity. Interestingly, hGMSCs exhibit not only multipotent differentiation and self-renewal capacities but also possess superior immunosuppressive effect as compared to bone marrow mesenchymal stem cells (BMMSC), by inducing Tregs expansion and inhibiting Th17 cells, and consequently, suppress tissue destruction in our inflammation-related tissue injury/osteonecrosis model induced by bisphosphonate (BRONJ). We hypothesize that GMSCs are capable of playing dual roles in tissue repair including a protective role as an immunomodulator to inhibit tissue injury and a tissue regeneration role through their multipotent differentiation capacities. In this application, our interdisciplinary team with advanced specialties in stem cell biology, immunology, tissue repair/regeneration, and clinical therapies, proposes to elucidate the molecular mechanisms of inflammation- related tissue injury/degeneration, and develop a novel therapeutic approach using GMSCs to suppress inflammation and promote regeneration/reconstruction of diseased and injured oral and craniofacial tissues. Our objective will be addressed using three integrated specific aims: 1) To further delineate stem cell properties of hGMSCs at the single colony level; 2) To determine whether hGMSCs are capable of immunomodulation and the underlying mechanisms; and 3) To explore the feasibility of targeting GMSCs to reduce inflammation and promote tissue regeneration in animal models of inflammation- related oral disorders/diseases. This study will substantially extend current knowledge of the immunomodulatory functions of GMSCs and provide critical pre-clinical data to test the feasibility and efficacy of novel therapeutic approach using GMSC to harness inflammation and enhance regeneration of inflammation-related or injured orofacial tissues.

项目概要/摘要 再生医学的一个主要障碍是解决与疾病相关的炎症和 优化组织再生能力，以防止继发于炎症或疾病的进一步组织破坏 疤痕。最近，间充质干细胞（MSC）研究取得重大突破，确定了一种内在的 MSCs 在免疫调节功能中的作用。我们已经证明促炎细胞因子 通过趋化因子和硝酸盐的协同作用实现 MSC 的免疫抑制功能所需 氧化物，并且激活的T细胞可以通过Fas/Fas L途径诱导MSCs凋亡。我们的学习也 研究表明，皮肤来源的间充质干细胞的免疫抑制特性受到局部环境的严格调控。 自分泌/旁分泌 IL17/IL6 轴介导的炎症生态位以及靶向治疗方法 这些独特的生态位成分导致了过度疤痕形成的抑制。基于这些 通过观察，我们探讨了从人牙龈 (hGMSC)（一种独特的口腔组织）中分离 MSC 的可行性 它既充当生物粘膜屏障，又充当口腔粘膜免疫的组成部分。 有趣的是，hGMSCs不仅表现出多能分化和自我更新能力，而且还具有 与骨髓间充质干细胞（BMMSC）相比，具有更好的免疫抑制作用 诱导 Tregs 扩增并抑制 Th17 细胞，从而抑制我们体内的组织破坏 双膦酸盐（BRONJ）诱导的炎症相关组织损伤/骨坏死模型。 我们假设 GMSC 能够在组织修复中发挥双重作用，包括作为组织修复的保护作用。 免疫调节剂通过多能分化抑制组织损伤和组织再生作用 能力。 在这个应用中，我们的跨学科团队在干细胞生物学、免疫学、组织学等方面拥有先进的专业知识。 修复/再生和临床治疗，旨在阐明炎症的分子机制 相关的组织损伤/变性，并开发一种利用 GMSC 抑制的新治疗方法 炎症并促进患病和受伤的口腔和颅面组织的再生/重建。 我们的目标将通过三个综合具体目标来实现：1）进一步描述干细胞 hGMSC 在单集落水平上的特性； 2) 确定 hGMSC 是否能够 免疫调节及其潜在机制； 3）探索目标的可行性 GMSCs 在炎症动物模型中减少炎症并促进组织再生 相关口腔疾病/疾病。 这项研究将大大扩展目前对 GMSC 和免疫调节功能的认识。 提供关键的临床前数据，以测试使用 GMSC 的新型治疗方法的可行性和有效性 利用炎症并增强炎症相关或受损的口面部组织的再生。