FGF-MAPK-PINK1介导线粒体自噬延缓人脂肪干细胞衰老

Senescence of adipose-derived stem cells (ADSCs) in vivo plays a critical role in human aging and directly impairs their therapeutic effects in the regenerative medicine. Thus, the regulation mechanism of aging and anti-aging become a key and cutting-edge scientific issue in the field of regenerative medicine. To date, there is lack of a thorough investigation into the regulation network underlying the maintenance of ADSC stemness and the ADSC aging, furthermore the systemic exploration of ADSC rejuvenation is extremely limited. We developed and characterized an in vitro system which can effectively model ADSCs aging and rejuvenation. Based on this system, we revealed that MAPK expression and mitophagy was dramatically decreased in the senescent ADSCs. By using high-throughput sequencing and systems biology, we further demonstrated that inhibition of MAPK activity in ADSCs impairs mitochondrial function and exacerbates senescence of ADSCs. More intriguingly, bFGF was found to attenuate the senescence of ADSCs, and the underlying mechanism is unknown at present. Further investigation showed that the supplement of bFGF to ADSCs increase MAPK expression and mitophagy, inferred the bFGF axis might regulate senescence of ADSCs, which involves the MAPK pathway and mitochondria. In this project, we will explore the molecular mechanism and network of ADSC senescence by the bFGF axis including MAPK pathway and mitophagy. We believe our work will provide new insights and theoretical basis for optimizing therapeutic effect of ADSCs and enhancing their application in regenerative medicine.

脂肪干细胞衰老在人衰老进程中发挥着关键作用，临床上衰老脂肪干细胞直接影响其移植治疗的效果，因此其衰老信号通路的调控机制和延缓衰老的研究是再生医学领域重大和前沿科学问题。迄今为止，对于脂肪干细胞干性维持和衰老的分子机理缺乏深入解析，而对其重编程年轻化的系统性探索更是空白。我们建立了一套脂肪干细胞体外衰老和年轻化的模拟系统，利用高通量测序的方法，我们发现衰老脂肪干细胞中MAPK和线粒体自噬等信号通路显著下调，并且进一步证实抑制MAPK的表达会损害线粒体功能，加剧脂肪干细胞衰老。更引人关注的是我们发现bFGF能延缓脂肪干细胞衰老，但是其延缓衰老的作用途径和机制目前未知。我们进一步研究发现bFGF能提高MAPK和线粒体自噬表达。据此，我们拟研究bFGF通过介导MAPK活性调控线粒体自噬水平延缓脂肪干细胞衰老的具体分子机制和调控网络，为优化脂肪干细胞治疗效果和促进其在再生医学领域应用提供新的思路。

脂肪干细胞衰老在人衰老进程中发挥着关键作用，临床上衰老脂肪干细胞直接影响其移植治疗的效果，因此其衰老信号通路的调控机制和延缓衰老的研究是再生医学领域重大和前沿科学问题。本课题组前期已经建立了一套脂肪干细胞体外衰老和年轻化的模拟系统。基于实验数据，我们发现衰老脂肪干细胞中MAPK和线粒体自噬等信号通路显著下调，而bFGF显著延缓脂肪干细胞衰老。并且进一步证实抑制MAPK和PINK1的表达会损害线粒体功能并加速脂肪干细胞衰老，而bFGF能显著上调脂肪干细胞MAPK和PINK1的表达。通过抑制剂和基因敲低的实验数据，我们发现分别抑制脂肪干细胞中RAF1和PINK1基因表达，能显著加速脂肪干细胞衰老。而在衰老脂肪干细胞中过表达PINK1基因表达，则显著延缓脂肪干细胞衰老。通过免疫共沉淀的数据证实脂肪干细胞RAF1和PINK1之间存在蛋白质相互作用，提示RAF1和PINK1之间相互作用在延缓脂肪干细胞衰老过程中起到关键作用。

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