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: 8070529
• 负责人: Anh D Le
• 金额: $ 57.43万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070529
• 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; Wound Healing; 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; public health relevance; reconstruction; regenerative; repaired; restoration; self-renewal; stem cell biology; stem cell population; tissue regeneration

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This study will explore the use of stem cells derived from the gingiva, a specialized oral tissue, to inhibit inflammation and its tissue destruction in order to develop an optimal approach for the repair and restoration of the injured orofacial tissues.

描述（由申请人提供）：再生医学的主要障碍是解决疾病相关炎症和优化组织再生能力的能力，以防止继发炎症或瘢痕形成的进一步组织破坏。最近，间充质干细胞（MSCs）的研究取得了重大突破，发现了MSCs在免疫调节功能中的内在作用。我们已经证明，通过趋化因子和一氧化氮的协同作用，促炎细胞因子是MSCs免疫抑制功能所必需的，激活的T细胞可以通过Fas/Fas L途径诱导MSCs凋亡。我们的研究还表明，皮肤源性MSCs的免疫抑制特性受到由自分泌/旁分泌IL17/IL6轴介导的局部炎症生态位的严格调节，针对这些不同生态位成分的治疗方法导致过度疤痕形成的抑制。基于这些观察结果，我们探索从人牙龈中分离MSCs （hGMSCs）的可行性，hGMSCs是一种独特的口腔组织，既是生物粘膜屏障，也是口腔粘膜免疫的一个组成部分。有趣的是，与骨髓间充质干细胞（BMMSC）相比，hGMSCs不仅表现出多能分化和自我更新能力，而且还具有优越的免疫抑制作用，通过诱导Tregs扩增和抑制Th17细胞，从而抑制双膦酸盐（BRONJ）诱导的炎症相关组织损伤/骨坏死模型中的组织破坏。我们假设GMSCs能够在组织修复中发挥双重作用，包括作为免疫调节剂抑制组织损伤的保护作用和通过其多能分化能力的组织再生作用。在本申请中，我们的跨学科团队在干细胞生物学、免疫学、组织修复/再生和临床治疗方面具有先进的专业知识，提出阐明炎症相关组织损伤/变性的分子机制，并开发一种利用GMSCs抑制炎症和促进患病和受伤的口腔和颅面组织再生/重建的新治疗方法。我们的目标将通过三个综合的具体目标来解决：1)在单个集落水平上进一步描述hGMSCs的干细胞特性；2)确定hGMSCs是否具有免疫调节能力及其机制；3)探讨靶向GMSCs在炎症相关口腔疾病动物模型中减少炎症和促进组织再生的可行性。这项研究将大大扩展目前对GMSC免疫调节功能的了解，并提供关键的临床前数据，以测试使用GMSC控制炎症和增强炎症相关或损伤的口面部组织再生的新治疗方法的可行性和有效性。