lncRNA NEAT1对红细胞分化的作用及机制研究

Nowadays, the widespread problems related to shortage of blood supply and transfusion -transmitted infections elicit an increasing demand for artificial blood. A promising alternative strategy to solve the “blood safety” problem is to induce the hematopoietic progenitor CD34+ cells differentiation into mature red blood cells in vitro. However, the use of produced RBCs in vitro still faces a number of challenges, such as insufficient self-renewal of the erythroid progenitors and enucleation of the erythroid precursors. Accumulating evidence indicates that some lncRNAs play important roles during the hematopoietic lineage differentiation processes. Our preliminary data suggested that lncRNA NEAT1 displayed a dynamic expression pattern during the differentiation of the hematopoietic progenitor CD34+ to erythroid lineage. In this proposal, we will continue to reveal the mechanism of NEAT1 regulation of erythroid differentiation using use Neat1 knock-out mice model and other technologies, which will help to optimize the current procedure to produce RBCs from cord blood CD34+ in vitro.

血源不足、输血安全是世界性难题。解决此难题的一个有效途径是在体外大量诱导产生具有生理功能的成熟红细胞。脱核效率低下是目前体外诱导产生成熟红细胞的最关键限速步骤之一。我们研究发现细胞核亚结构旁斑的关键组成因子lncRNA NEAT1在人红细胞分化过程中表达呈动态变化，以晚幼红细胞表达值最高。同时，在脐带血CD34+诱导分化的红细胞中发现NEAT1促进红细胞的脱核。本研究将在此基础上，利用Neat1基因敲除小鼠，检测NEAT1在红细胞分化中的功能及作用。此外，我们将利用RIP，RNA-pulldwon，ChIRP等技术继续阐明NEAT1促进红细胞脱核的机制，以期为体外大量生产成熟红细胞提供理论基础。

越来越多功能研究表明，lncRNAs在生理和病理条件下发挥着重要作用。在本研究中，我们发现体外lncRNA Neat1的缺失会抑制人脐带血CD34+细胞向红系分化，体内稳态条件缺失Neat1会抑制脾脏的红系分化。RNA-seq数据显示，Neat1缺失主要抑制脾脏中红系血红素合成相关基因的表达。另一方面，Neat1对PHZ诱导的急性溶血性贫血模型小鼠的骨髓和脾脏红细胞生成无影响。综上所述，我们的研究揭示了lncRNA Neat1的一个新发现功能，即通过调节体内血红素的合成来影响红细胞发育。