间充质干细胞（MSC）具有免疫调节、多向分化及造血支持等功能，是临床细胞治疗的重要工具，但细胞老化能削弱甚至抑制MSC的治疗作用。因此，研究MSC老化及机制具有重要临床价值。我们前期研究发现，静脉输注体外扩增的MSC不能缓解内毒素血症模型的组织炎性损伤，甚至有加重趋势。那么，体内炎症微环境是否通过诱导MSC老化而损伤MSC的正常功能？其潜在机制是什么？至今尚无相关的系统研究报道。为此，我们将利用内毒素血症模型血清模拟体内炎症微环境，探讨其对MSC老化的影响；并以Notch1信号通路为切入点，结合基因过表达和沉默技术，研究Notch1通路活化在炎症微环境诱导MSC老化中的作用；进一步研究老化相关分子SIRT1和转录因子NF-κB、C/EBPβ是否分别在Notch1通路的上、下游共同调节MSC老化。本研究旨在阐明炎症微环境对MSC老化的作用及机制，为寻找优化MSC质量的方法提供实验和理论依据。

Mesenchymal stem cells (MSC) serve as important tools for cell therapy in clinic, owned to their functions in immunoregulation, mulitple lineage differentiation potential as well as support of hematopoiesis. However, senescence can impair or inhibit therapeutic function of MSC. Therefore, it is of great importance to investigate senescence of MSC and its potential mechanisms. Our previous study showed that infusion of in vitro expanded MSC couldn’t ameliorate endotoxemic tissue injuries, and they could even aggravate the inflammatory response. We asked whether in vivo inflammatory microenvironment could impair biological functions of MSC through induction of cell senescence, and what is the potential mechanism. These questions remains to be clarified till now. For this reason, we try to mimic the in vivo inflammatory microenvironment with serum from endotoxemia models, and investigate effects of inflammatory microenvironment on senescence of MSC. Then, we will focuse on Notch1 signaling pathway to clarify the role of Notch1 signaling in inflammation-induced MSC senescence, by making use of RNA silencing and overexpression technique. Finally, we will investigate whether sencescence-associated SIRT1 and transcription factor NF-κB、C/EBPβ can regulate MSC senescence in the upstream and downstream of Notch1 respectively. The main purpose of this study is to clarify the effects of inflammatory microenvironment on MSC senescence and the mechanisms underlined. It will provide experimental and theoretical evidence for exploring ideal means to optimize quality of MSC, and thus to obtain better outcomes in clinical trials of cell therapy.