AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate

作者：Qilin Gu, Xiaojie Yang, Jie Lv, Jiaxiong Zhang, Bo Xia, Jun‐Dae Kim, Ruoyu Wang, Feng Xiong, Shu Meng, Thomas P. Clements, Bhavna Tandon, Daniel S. Wagner, Miguel F. Diaz, Pamela L. Wenzel, Yury I. Miller, David J. Traver, John P. Cooke, Wenbo Li, Leonard Ira Zon, Kaifu Chen, Yongping Bai, Longhou Fang · 发表于：Science · 年份：2019 · DOI：10.1126/science.aav1749 · 被引用次数：126 · 研究领域：Zebrafish Biomedical Research Applications、Immune Cell Function and Interaction、Epigenetics and DNA Methylation

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 up-regulation 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.