YY1通过SENP1/ HIF-1α介导的抗干细胞凋亡作用提高干细胞移植对心肌梗死疗效的研究

Stem cells transplantation is a promising therapy for myocardial infarction (MI), but it is limited to the poor survival due to the hypoxic condition in infarcted myocardium. Hif-1α can promote cell survival under hypoxia, but it is subject to degradation. Previous studies reported that SUMOylation is an important modification regulating Hif-1α degradation. Our previous work suggested that transcriptional factor Yinyang1 (YY1) promotes mesenchymal stem cells (MSCs) survival under hypoxia, and that YY1 can stabilize Hif-1α possibly via Sentrin/SUMO-specific protease 1 (SENP1). Therefore we hypothesize that YY1 promotes MSCs survival under hypoxia and improve the therapeutic effect of transplantation by stabilizing Hif-1α, this effect is possibly due to the binding of YY1 to SENP1 promoter, up-regulation of SENP1, and the consequent Hif-1α de-SUMOylation. Our project aimed to reveal the mechanism underlying how YY1 stabilize Hif-1α, and to provide a novel therapeutic target for stem cell strategy for MI.

干细胞移植是治疗心肌梗死研究的重要方向，但缺血缺氧微环境引起移植后干细胞大量凋亡，导致干细胞存活率低下并限制其治疗效果。缺氧诱导因子1α（HIF-1α）是提高干细胞缺氧耐受能力的关键分子，但是HIF-1α极易降解，最近研究发现SUMO化修饰是影响HIF-1α降解的重要调控方式。我们的前期工作提示转录因子Yinyang-1（YY1）可促进间充质干细胞在缺氧条件下的存活，并且YY1可抑制HIF-1α的降解，这一现象可能与SUMO蛋白酶SENP1有关。由此我们提出假设：YY1通过上调SENP1的转录，影响HIF-1α的SUMO化从而抑制其降解，提高移植后干细胞的存活及其对心肌梗死的疗效。本项目旨在揭示YY1通过蛋白修饰抑制HIF1-α降解的分子机制，为提高干细胞移植治疗心肌梗死提供新的干预靶点。