内质网应激在间充质干细胞老化过程中的作用及其机制研究

The dysfunction of stem cells are triggered by aging or premature senescence, causes the degradation of tissue regeneration. However, the mechanism of stem cell aging and senescence is not fully known. Our previous studies suggested that the activity of telomerase was significantly decreased in the aging stem cells, but the mechanism is unknown. As an evolutionary conserved mechanism, endoplasmic reticulum stress (ERS) regulates the activity of telomerase. Hence, the hypothesis is arised that the activity of telomerase is regulated by aging mesenchymal stem cells (MSC) through ERS pathway, protect MSC from the premature senescence or aging by control the ERS pathway. Therefore, differentiated iPSCs from Werner Syndrome patients to mesenchymal stem cells (MSCs) exhibits the phenotype of aging or senescence, and deficiency the WRN protein. Based on the successful construct the aging model, the related molecular methods are used to explore the function of ERS in the MSCs aging, explore the mechanism of ERS in the MSCs aging. Furthermore, based on the revealing the function and mechanism of ERS in the MSCs aging, the premature aging or senescence could be relieved or inhibited by control ERS levels, and give a novel insights to prevent and protect dysfunction of tissue regeneration.

老化使得干细胞的功能丧失，进而导致组织再生功能退化。然而，干细胞老化的作用机制目前还未完全揭示清楚。我们前期的研究结果揭示老化的干细胞端粒及端粒酶活性显著降低，但是其影响端粒长度及端粒酶活性的机制还不清楚。内质网应激作为一种进化保守性机制，参与调控端粒。故推测：老化的间充质干细胞激活内质网应激信号进而影响端粒活性，通过对内质网应激信号通路的干预可以抑制干细胞的老化。因此，本研究在成功构建的WRN基因缺失所致老化的间充质干细胞模型基础之上，应用相关分子生物学方法研究内质网应激在WRN基因缺失老化的间充质干细胞中的作用，研究内质网应激在间充质干细胞老化过程中对端粒酶活性的影响。通过研究的进行，揭示内质网应激在WNR基因缺失所致老化干细胞中的作用及其机制。进而通过调控内质网应激抑制间充质干细胞的老化，对于临床治疗及预防组织再生功能障碍具有重要的指导意义。

老化使得干细胞的功能丧失，进而导致组织再生功能退化。然而，干细胞老化的作用机制目前还未完全揭示清楚。我们前期的研究结果揭示老化的干细胞端粒及端粒酶活性显著降低，但是其影响端粒长度及端粒酶活性的机制还不清楚。内质网应激作为一种进化保守性机制，参与调控端粒。故推测：老化的间充质干细胞激活内质网应激信号进而影响端粒活性，通过对内质网应激信号通路的干预可以抑制干细胞的老化。因此，本研究在成功构建的WRN基因缺失所致老化的间充质干细胞模型基础之上，应用相关分子生物学方法研究内质网应激在WRN基因缺失老化的间充质干细胞中的作用，研究内质网应激在间充质干细胞老化过程中对端粒酶活性的影响。通过研究的进行，揭示内质网应激在WNR基因缺失所致老化干细胞中的作用及其机制。进而通过调控内质网应激抑制间充质干细胞的老化，对于临床治疗及预防组织再生功能障碍具有重要的指导意义。