Hoxb5促进多潜能造血祖细胞长期重构造血的机制研究

多潜能造血祖细胞（MPP）能快速分化成所有的造血谱系，在骨髓移植早期应急造血中起关键作用，但不具备自我更新能力。因此，通过改造MPP的活性来改善造血植入是重要的研究思路。前期研究显示在MPP中过表达Hoxb5，能够实现系列移植并长期稳定造血。进一步对细胞进行分群移植，发现了Mac-1+CD48+LSK新表型细胞。基于上述发现，本研究拟利用Hoxb5小鼠模型，通过移植天然表型MPP（Mac-1-CD48-LSK）再启动Hoxb5表达，证明Mac-1+CD48+LSK细胞在造血层级中的起源定位，并明确这群细胞的长期造血功能。进一步利用小鼠模型，通过RNAseq，ATAC-seq，Chip-seq等技术，在转录组和表观遗传学水平上深入探究Hoxb5对MPP造血生成影响的分子机制。该研究将阐明Hoxb5促进多潜能造血祖细胞长期重构造血的机制，为开发新手段操纵MPP促进植入和长期造血提供理论依据。

Multipotent progenitor cells (MPP) can immediately reconstitute all the hematopoietic lineages after transplantation, and play an essential role in early hematopoiesis after bone marrow transplantation. However, The self-renewal ability of MPP is not preserved during HSC differentiation. Therefore, it is important to modify the MPP to improve its reconstitute capacity. Our unpublished data has shown that Hoxb5-expressing MPP obtained the long-term hematopoiesis capacity, and generated self-renewable Lin-sca1+c-kit+ cells (LSK) which expressing Mac-1 and CD48 (Mac-1+CD48+LSK) simultaneously. Based on this finding, we will find out the derivation and functional role of the Mac-1+CD48+LSK with Hoxb5 knock in models (Hoxb5LSL/+Mx1cre, Tet-Hoxb5), and the Mac-1+CD48+LSK will be produced by the recipients transplanted with the wide type phenotype MPP (Mac-1-CD48-LSK). Moreover, second transplantation will be performed to further confirm the long-term reconstitution ability of the Mac-1+CD48+LSK. Furthermore, we’ll also find out the molecular mechanisms in terms of transcriptome and epigenetics using RNA-seq, ATAC-seq and Chip-seq technology with BirALSL/+Bio-Hoxb5LSL/+Mx1cre model. Our research will not only reveal the mechanisms of long-term hematopoiesis ability in the Hoxb5-expressing MPP, but can also provide theoretical basis to develop news methods to empower the MPP long-term hematopoiesis ability.