GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION

项目总结/摘要 再生医学的一个主要障碍是解决疾病相关炎症的能力， 优化组织再生能力，以防止继发于炎症的进一步组织破坏，或 疤痕最近，间充质干细胞（MSC）研究的重大突破确定了一种内在的 MSC在免疫调节功能中的作用。我们已经证明，促炎细胞因子是 所需的免疫抑制功能的间充质干细胞通过协调行动的趋化因子，和硝酸 活化的T细胞可通过Fas/Fas L途径诱导MSCs凋亡。我们的研究还 已经揭示了皮肤来源的MSC的免疫抑制特性受到局部免疫调节。 自分泌/旁分泌IL 17/IL 6轴介导的炎症生态位，以及靶向治疗方法 这些独特的小生境组分导致过度瘢痕形成的抑制。基于这些 观察，我们探讨了从人牙龈（hGMSCs），一个独特的口腔组织分离间充质干细胞的可行性 其既作为生物粘膜屏障又作为口腔粘膜免疫的组分起作用。 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，通过以下方法获得上级免疫抑制效果： 诱导Th 17细胞扩增并抑制Th 17细胞，从而抑制我们的组织破坏。 炎症相关的组织损伤/骨坏死模型由双膦酸盐（BRONJ）诱导。 我们假设GMSC在组织修复中能够发挥双重作用，包括作为一种保护性作用， 免疫调节剂通过其多能分化抑制组织损伤和组织再生作用 能力。 在这项应用中，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，提出阐明炎症的分子机制- 相关的组织损伤/变性，并开发一种新的治疗方法，使用GMSC来抑制 炎症并促进患病和受伤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解决：1）进一步描述干细胞 hGMSC在单集落水平的特性; 2）为了确定hGMSC是否能够 免疫调节及其机制; 3）探讨靶向治疗的可行性 GMSC在炎症动物模型中减少炎症并促进组织再生- 相关的口腔疾病/病症。 这项研究将大大扩展目前对GMSC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， 控制炎症并增强炎症相关或受损口面组织的再生。

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.