GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION

项目摘要/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，防止因炎症或其他原因继发的组织破坏 伤痕累累。最近，间充质干细胞(MSCs)研究的一项重大突破确定了一种内在的 骨髓间充质干细胞在免疫调节功能中的作用我们已经证明了促炎细胞因子是 趋化因子和一氧化氮协同作用对间充质干细胞免疫抑制功能的影响 激活的T细胞可通过Fas/Fas L途径诱导MSCs的凋亡。我们的研究也 已发现皮肤来源的MSCs的免疫抑制特性受到局部组织的严格调控 自分泌/旁分泌IL17/IL6轴介导的炎症生态位及其靶向治疗 这些独特的利基成分抑制了过度的疤痕形成。基于这些 通过观察，我们探索了从独特的口腔组织--人牙周组织中分离间充质干细胞的可行性。 这既是一种生物粘膜屏障，也是口腔粘膜免疫的一个组成部分。 有趣的是，hGMSCs不仅具有多向分化和自我更新的能力，而且还具有 优于骨髓间充质干细胞(BMMSC)的免疫抑制作用，通过 诱导Tregs扩张并抑制Th17细胞，从而抑制我们的组织破坏 双膦(BRONJ)诱导的炎症相关组织损伤/骨坏死模型。 我们假设GMSCs能够在组织修复中发挥双重作用，包括作为一种保护作用 免疫调节剂通过其多能分化抑制组织损伤和组织再生的作用 容量。 在这项应用中，我们的跨学科团队拥有干细胞生物学、免疫学、组织学等高级专业知识 修复/再生和临床治疗，建议阐明炎症的分子机制- 相关组织损伤/退变，并开发一种使用GMSCs抑制 发炎和促进病变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的具体目标来实现：1)进一步描述干细胞 HGMSCs在单个集落水平的特性；2)确定hGMSCs是否有能力 免疫调节及其机制；3)探讨靶向治疗的可行性 GMSCs在炎症动物模型中减轻炎症并促进组织再生- 相关的口腔疾病/疾病。 这项研究将大大扩展目前对GMSCs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的新治疗方法的可行性和有效性 治疗炎症并促进炎症相关或受伤的口腔组织的再生。

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.