内皮细胞造血转化负调控分子的筛选及相关机制研究

Hematopoietic stem cells (HSC) are capable of self-renew and differentiation into all blood cell types. It is well acknowledged that HSCs arise from hemogenic endothelial cells, the process is called endothelial-hematopoietic transition (EHT). However, the underlying mechnism of EHT is still poorly understood, this largely due to the absence of proper cell surface marker. Forturnately, we discover that CD43 specifically and faithfully marks the EHT, and provides us a good way to understand the regulation of EHT. In this study, we sought to reveal the negative regulation of EHT through the following steps: a) Find out the universal transcription factor (TF) X that negative modulate EHT in all known embryonic hematopoietic sites including AGM region, yolk sac and placenta, b) Clarify the hematopoietic phenotype differences caused by TF X knock-down or over-expression, c) Uncover the underlying molecular mechanism of TF X induced hematopoietic phenotype alteration. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provide us an opportunity for regenerative therapy based on immunologically compatible cells, down regulation of TF X could faciliate EHT cell fate selection in ESCs and iPSCs, therefore enable the ESCs/iPSCs based regenerative therapy.

造血干细胞具有自我更新能力和各系造血分化潜能，它最早出现于胚胎发育期背主动脉腹侧的血管内皮细胞。尽管研究表明造血细胞来自于生血内皮，但是由于缺少特异性细胞表面标记，严重限制了对定向造血起始阶段内皮细胞造血转化(EHT)的分子机制研究及可能的再生医学应用研究。前期工作中我们发现CD43可以标示EHT，本研究中我们拟以CD43为手段，探索EHT的负调控机制：1）寻找胚胎发育不同造血位点（卵黄囊、胎盘、AGM区）EHT的通用负调控因子X，2）该转录因子X在EHT过程中发挥的生物学作用，及可能的再生医学应用，3）研究转录因子X负调控EHT的分子机制。胚胎干细胞(ESCs)和诱导性多潜能干细胞（iPSCs）是目前再生医学研究的热点，下调EHT负调控因子TF X可以促进以上多能干细胞EHT过程，这将为以自体ESCs/iPSCs体外诱导造血分化为基础的再生医学研究提供理论参考。