AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate
AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate
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DOI：
10.1126/science.aav1749
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发表时间：
2019-03-08
期刊：
影响因子：
56.9
通讯作者：
Fang, Longhou
中科院分区：
文献类型：
--
作者：
Gu, Qilin;Yang, Xiaojie;Fang, Longhou
高胆固醇血症，动脉粥样硬化的驱动力，加速造血干细胞和祖细胞（HSPCs）的扩增和动员。连接高胆固醇血症与造血的分子决定因素尚不清楚。在这里，我们报告了一个体节衍生的促造血因子，AIBP，协调HSPC出现从造血内皮细胞，一种专门的内皮细胞表现出造血潜力。在机制上，AIBP介导的胆固醇流出激活内皮Srebp 2，胆固醇生物合成的主转录因子，这反过来反式激活Notch并促进HSPC出现。Srebp 2抑制损害高胆固醇血症诱导的HSPC扩增。Srebp 2激活和Notch上调与高胆固醇血症人类受试者中的HSPC扩增相关。全基因组染色质免疫沉淀，然后测序（ChIP-seq）、RNA测序（RNA-seq）和使用测序（ATAC-seq）进行转座酶可及染色质分析表明，Srebp 2反式调节造血所需的Notch途径基因。我们的研究概述了动脉粥样硬化性心血管疾病中HSPC在发育中出现和HPSC扩增的AIBP调节的Srebp 2依赖性范例。
Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch upregulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.