INTERPLAYS BETWEEN THE JAW MESENCHYMAL STEM CELLS AND T LYMPHOCYTES

描述(申请人提供)：骨髓间充质干细胞(BMMSCs)是一种多能干细胞，能够分化为不同的谱系细胞，包括成骨细胞、软骨细胞、脂肪细胞、心肌细胞、成肌细胞和神经细胞。最近的一项重大突破是发现BMMSCs对T细胞具有深刻的抑制作用。而我们的初步研究表明，活化的T细胞能够通过Fas/FasL途径诱导BMMSC凋亡，提示T细胞与BMMSCs之间存在一种新的串扰机制。免疫性疾病的目标是具有特殊表型的口面部骨骼，如牙周病、甲状旁腺功能亢进症和颌骨肿瘤综合征。此外，口腔颌骨中含有骨髓间充质干细胞(OFMSCs)，在分化特性和组织再生特性上与BMMSCs不同。因此，这一应用的目的是探索T细胞是否以及如何调节OFMSCs，以及这种调节是否有助于口腔颌面部骨骼疾病。我们的初步研究证实，我们能够分离和扩增小鼠OFMSCs，这使得我们能够利用小鼠模型来研究OFMSCs和T细胞之间的相互作用。这一成果对所提出的研究至关重要，因为分离和扩增小鼠OFMSCs是困难的，并且依赖于干细胞培养经验。我们的初步数据表明，小鼠OFMSCs在体外对T细胞活性的抑制作用不同于BMMSCs。我们的假设是，T细胞对OFMSCs的调节方式与T细胞和BMMSCs之间的相互作用不同，这可能与免疫性疾病的口腔面骨表型有关。在这项应用中，我们将以骨髓间充质干细胞为对照，探索T细胞如何与OFMSCs相互作用。此外，我们还将研究T细胞介导的OFMSC反应是否参与口腔面部免疫疾病的表型，如卵巢切除引起的T细胞过度激活的骨质疏松症。最后，我们将评估全身输注OFMSC是否能对T细胞过度激活障碍起到治疗作用。综上所述，我们的新发现将为理解T细胞和OFMSCs之间的相互作用提供细胞和分子基础。这些数据可能会导致在识别与口面部骨骼相关的免疫疾病机制方面的新知识。项目简介：这项研究的目的是了解口腔面部间充质干细胞和免疫细胞之间的串扰，并描述这种串扰可能与口腔面部骨骼疾病相关的机制。我们将利用这些知识来探索治疗口腔颌面部骨病的新方法。

DESCRIPTION (provided by applicant): Bone marrow mesenchymal stem cells (BMMSCs) are multipotent stem cells capable of differentiating into different lineage cells including osteoblasts, chondrocytes, adipocytes, cardiomyocytes, myoblasts, and neural cells. A recent major breakthrough was the discovery that BMMSCs exert a profound inhibitory effect on T cells. While our preliminary studies revealed that activated T cells are capable of inducing BMMSC apoptosis through the Fas/FasL pathway, suggesting a novel crosstalk mechanism between T cells and BMMSCs. Immune diseases target the orofacial bones with specific phenotypes as seen in periodontal diseases, cherubism, and hyperparathyroid jaw tumor syndrome. Moreover, the orofacial jaw bones contain MSCs (OFMSCs) that are distinct to BMMSCs in terms of differentiation traits and tissue regeneration characteristics. Therefore, the objective of this application is to explore whether and how T cells regulate OFMSCs and whether this regulation contributes to orofacial bone disorders. Our preliminary studies identified that we are able to isolate and expand mouse OFMSCs, which allow us to use mouse models to study the interplay between OFMSCs and T cells. This achievement is critical for the proposed studies because isolation and expansion of mouse OFMSCs are difficult and reliant on stem cell culture experience. Our preliminary data showed that mouse OFMSCs differ from BMMSCs in inhibiting T cell activities in vitro. Our hypothesis is that T cells regulate OFMSCs in a way distinctive from those discovered in the interplays between T cells and BMMSCs, which may link to the orofacial bone phenotypes of immune diseases. In this application, we will explore how T cells interplay with OFMSCs using BMMSCs as a comparison. Moreover, we will examine whether T cell-mediated OFMSC response involved in orofacial phenotypes of immune diseases such as T cell over-activated osteoporosis induced by ovarioectomy. Finally, we will assess whether systemic OFMSC infusion can offer therapeutic effect on T cell over-activated disorders. In summary, novel findings from our proposed studies will provide cellular and molecular basis for understanding interplays between T cells and OFMSCs. These data are likely to lead to new knowledge on identifying mechanisms of immune disorders associated with the orofacial bones. Project Narrative: The purpose of this study is to understand crosstalk between orofacial mesenchymal stem cells and immune cells and delineate the mechanisms by which the crosstalk may associate with orofacial bone diseases. We will use this knowledge to explore new approaches for orofacial bone disease treatment.