INTERPLAYS BETWEEN THE JAW MESENCHYMAL STEM CELLS AND T LYMPHOCYTES

描述（由申请人提供）：骨髓间充质干细胞（BMMSCs）是一种多能干细胞，能够分化为不同谱系的细胞，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骨髓间充质干细胞对T细胞具有深远的抑制作用。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，这表明T细胞和BMMSC之间存在一种新的串扰机制。免疫性疾病以具有特定表型的口面骨为靶点，如牙周病、小天使病和甲状旁腺功能亢进颌骨肿瘤综合征。此外，口腔颌面骨含有MSCs (OFMSCs)，在分化特征和组织再生特征方面与BMMSCs不同。因此，本应用的目的是探讨T细胞是否以及如何调节OFMSCs，以及这种调节是否有助于口面骨疾病。我们的初步研究表明，我们能够分离和扩增小鼠OFMSCs，这使我们能够使用小鼠模型来研究OFMSCs与T细胞之间的相互作用。这一成就对于拟建的研究至关重要，因为小鼠OFMSCs的分离和扩增是困难的，并且依赖于干细胞培养经验。我们的初步数据表明，小鼠OFMSCs在体外抑制T细胞活性方面与BMMSCs不同。我们的假设是，T细胞调节OFMSCs的方式不同于在T细胞和BMMSCs之间的相互作用中发现的方式，这可能与免疫疾病的口面骨表型有关。在本应用中，我们将以BMMSCs为对照，探讨T细胞如何与OFMSCs相互作用。此外，我们将研究T细胞介导的OFMSC反应是否参与卵巢切除术引起的T细胞过度活化骨质疏松等免疫疾病的口面部表型。最后，我们将评估全身OFMSC输注是否能对T细胞过度激活疾病提供治疗效果。总之，我们提出的研究的新发现将为理解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识别与口面骨相关的免疫疾病机制的新知识。项目描述：本研究的目的是了解口面间充质干细胞和免疫细胞之间的串扰，并描述串扰与口面骨疾病相关的机制。我们将利用这些知识来探索治疗口面骨疾病的新方法。

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.