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

基本信息

批准号：
7851425
负责人：
Anh D Le
金额：
$ 59.75万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/7851425
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 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

项目摘要

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）：再生医学的一个主要障碍是解决与疾病相关的炎症并优化组织再生能力以防止继发于炎症或疤痕的进一步组织破坏的能力。最近，间充质干细胞（MSC）研究的重大突破确定了 MSC 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 MSC 免疫抑制功能所必需的，并且活化的 T 细胞可以通过 Fas/Fas L 途径诱导 MSC 凋亡。我们的研究还表明，皮肤来源的 MSC 的免疫抑制特性受到自分泌/旁分泌 IL17/IL6 轴介导的局部炎症生态位的严格调节，针对这些独特的生态位成分的治疗方法可抑制过度疤痕形成。基于这些观察，我们探讨了从人牙龈 (hGMSC) 中分离 MSC 的可行性，人牙龈是一种独特的口腔组织，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，hGMSC 不仅表现出多能分化和自我更新能力，而且与骨髓间充质干细胞 (BMMSC) 相比，通过诱导 Tregs 扩增和抑制 Th17 细胞，从而抑制炎症中的组织破坏，从而具有优异的免疫抑制作用。双膦酸盐（BRONJ）诱导的相关组织损伤/骨坏死模型。我们假设 GMSC 能够在组织修复中发挥双重作用，包括作为抑制组织损伤的免疫调节剂的保护作用和通过其多能分化能力发挥组织再生作用。在此应用中，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拥有先进的专业知识，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 GMSC 来治疗炎症的新型治疗方法。抑制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）在单集落水平上进一步描述 hGMSC 的干细胞特性； 2）确定hGMSC是否具有免疫调节能力及其机制； 3) 探讨在炎症相关口腔病症/疾病的动物模型中靶向 GMSC 来减轻炎症并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 控制炎症并增强炎症相关或受损口面部组织再生的新治疗方法的可行性和功效。公共健康相关性：本研究将探索使用源自牙龈（一种特殊的口腔组织）的干细胞来抑制炎症及其组织破坏，以开发修复和恢复受损口面部组织的最佳方法。