REVERSAL OF MUCOSITIS BY GMSC-BASED THERAPY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 南加州大学牙医学院颅面分子生物学中心 消化道粘膜炎(AT)是化疗、骨髓移植和头颈部大剂量放射治疗的癌症患者的一种衰弱的副作用。我们实验室最近的研究从牙龈中分离出了一种新的干细胞群体，即GMSC，它是一种容易获得的组织来源，不仅具有多向分化和自我更新的能力，而且具有明显的免疫调节功能。GMSC基于细胞的治疗显著改善了实验性小鼠结肠炎的临床和组织病理学严重程度，可能是通过抑制炎性浸润物，特别是白介素17(IL-17)分泌细胞和大量炎性细胞因子/介质，并在结肠部位招募调节性T细胞(Tregs)。在另一种由化疗引起的粘膜炎症的疾病模型中，我们观察到，在接受GMSC一次探索性治疗的小鼠中，AT粘膜炎显著逆转，体重恢复近100%。 实验方法：我们将通过体外和体内研究来研究GMSC对Treg和Th17功能的免疫调节作用以及它们在粘膜炎中的作用。光学相干断层扫描(OCT)结合多光子显微镜(MMP)技术将被用来破译干细胞归巢到粘液部位。我们将测试适应性泛T细胞移植、体外扩增的Tregs和药物免疫增强疗法是否可以逆转粘膜损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California Mucositis of the alimentary tract (AT) is a debilitating side effect of cancer therapies in a high percentage of patients receiving chemotherapy, bone marrow transplantation, and high-dose radiation to the head and neck.Recent studies from our laboratory have isolated a new population of stem cells from human gingiva, an easily accessible tissue source, namely GMSC, which exhibit not only multipotent differentiation and self-renewal capacities, but also possess distinct immunomodulatory functions. Cell-based therapy with GMSC significantly ameliorated both clinical and histopathological severities of the colonic inflammation in the experimental murine colitis, presumably by suppressing inflammatory infiltrates, specifically interleukin-17 (IL-17) secreting cells, and a myriad of inflammatory cytokines/mediators, and recruiting regulatory T cells (Tregs) at the colonic sites. In another disease model of mucosal inflammation induced by chemotherapy, we observed a significant reversal of AT mucositis and regain of body weight in nearly 100% of mice undergoing an exploratory one dose treatment with GMSC Experimental Approaches: We will examine the immunomodulatory effects of GMSC on Treg and Th17 functions and how they contribute to mucositis using both in vitro and in vivo studies. Optical coherence tomography (OCT) coupled with multiphoton microscopy (MMP) technology will be utilized to decipher stem cell homing to mucositic sites. We will test whether adaptive transfer with Pan-T cells, ex vivo expanded Tregs, and pharmacologic immune boosting therapies can reverse mucosal injuries.