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.

项目摘要/摘要 再生医学中的主要障碍是解决与疾病相关的炎症和 优化组织再生能力，以防止炎症继发的进一步的组织破坏或 疤痕。最近，间充质干细胞（MSC）研究的重大突破确定了固有的 MSC在免疫调节功能中的作用。我们已经证明了促炎性细胞因子是 MSC通过趋化因子的一致作用和一氮的免疫抑制功能所必需的 氧化物，活化的T细胞可以通过FAS/FAS L途径诱导MSC凋亡。我们的研究也是如此 已经揭示了皮肤衍生的MSC的免疫抑制特性受到局部的严格调节 由自分泌/旁分泌IL17/IL6轴介导的炎症利基和靶向治疗方法 这些独特的小众组成部分导致抑制过多的疤痕形成。基于这些 观察结果，我们探索了从人牙龈（HGMSC）分离MSC的可行性，这是一种独特的口腔组织 这既是生物粘膜屏障，也是口服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，而且还具有 与骨髓间充质干细胞（BMMSC）相比 诱导Treg扩展并抑制Th17细胞，因此，抑制了我们的组织破坏 双膦酸盐（BRONJ）诱导的与炎症相关的组织损伤/骨坏死模型。 我们假设GMSC能够在组织修复中发挥双重作用，包括保护作用 免疫调节剂可通过其多能分化来抑制组织损伤和组织再生作用 能力。 在此应用中，我们的跨学科团队具有干细胞生物学，免疫学，组织的高级专业 修复/再生和临床疗法建议阐明炎症的分子机制 相关的组织损伤/变性，并使用GMSC抑制一种新型的治疗方法 炎症并促进患病和受伤的口腔和颅面组织的再生/重建。 我们的目标将使用三个集成的特定目的来解决：1）进一步描述干细胞 HGMSC在单个菌落水平上的特性； 2）确定HGMSC是否能够 免疫调节和潜在机制； 3）探索目标的可行性 GMSCs减少炎症并促进组织再生的炎症模型 相关的口腔疾病/疾病。 这项研究将大大扩展有关GMSC的免疫调节功能的当前知识 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功效 线束炎症并增强与炎症相关或受伤的口面组织的再生。