下调p38MAPKα-Mitf-嘌呤与mTORC1-SREBP1-脂质合成轴阻止扩增人HSCs的衰老以维持干性

造血干细胞（HSCs）数量不足限制其广泛应用，体外扩增有望解决此问题，但现有方案难以维持其干性。我们以往研究(NSFC 30871097# ，81170524#)证明：①扩增HSCs衰老是其干性丧失的机制之一；②分化抑制剂（SR1）扩增的HSCs存在p38丝裂原活化蛋白激酶α（P38MAPKα）和哺乳动物雷帕霉素靶蛋白（mTORC1）的活化，两者的联合下调可抑制其衰老并改善短期造血重建；③两者的联合下调也可降低扩增HSCs的小眼相关转录因子（Mitf）和胆固醇调节元件结合蛋白（SREBP1）水平。文献证实：高水平的Mitf和SREBP1可分别通过上调嘌呤和脂质合成诱导衰老，为此本项目拟研究：联合下调活化的P38MAPKα和mTORC1能否维持SR1扩增的HSCs长期造血重建能力，是否通过p38MAPKα-Mitf-嘌呤与mTORC1-SREBP1-脂质合成轴的下调阻止扩增HSCs的衰老。

The widely application of hematopoietic stem cells (HSCs) is restricted due to the insufficient cell numbers. Although HSCs could be obtained via ex vivo expansion,their stemness fails to be maintained by current expansion regimens.Our previous projects (NSFC 30871097# and 81170524#) have confirmed that：①the senescence is one of the mechanisms of the stemness damage in expanded HSCs;②the activation of both p38 mitogen activated protein kinase α(P38MAPKα) and complex 1 of the mammalian target of rapamycin (mTORC1) is still observed in StemRegenin 1 (SR1,a differentiation inhibitor) expanded HSCs,and the down-regulation of both P38MAPKα and mTORC1 could inhibit senescence and improve short-term hematopoietic reconstitution capability of the expanded HSCs;③the combined down-regulation of P38MAPKα and mTORC1 also decreases the expression of microphthalmia-associated transcription factor (Mitf) and sterol regulatory element binding protein 1 (SREBP1) in ex vivo expanded HSCs.Current studies have proved that cellular senescence could be induced through up-regulating purine and lipid synthesis performed by increased expression of Mitf and SREBP1 respectively. Therefore, the following questions will be investigated in this project:①whether the long term hematopoietic reconstitution ability of SR1 expanded HSCs could be maintained through down-regulation of both P38MAPKα and mTORC1 activities;②whether the senescence of expanded HSCs is prevented through the down-regulation of both p38MAPKα-Mitf-purine and mTORC1-SREBP1-lipid synthesis axes.