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

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6431; pp. 1085 - 1088
• Main Authors: Gu, Qilin, Yang, Xiaojie, Lv, Jie, Zhang, Jiaxiong, Xia, Bo, Kim, Jun-Dae, Wang, Ruoyu, Xiong, Feng, Meng, Shu, Clements, Thomas P, Tandon, Bhavna, Wagner, Daniel S, Diaz, Miguel F, Wenzel, Pamela L, Miller, Yury I, Traver, David, Cooke, John P, Li, Wenbo, Zon, Leonard I, Chen, Kaifu, Bai, Yongping, Fang, Longhou
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 08-03-2019
• Subjects: Animals; Anticholesteremic Agents - pharmacology; Arteriosclerosis; Atherosclerosis; Atorvastatin - pharmacology; Base Sequence; Biosynthesis; Cardiovascular disease; Cardiovascular diseases; Cell fate; Cells (biology); Cholesterol; Cholesterol - biosynthesis; Chromatin; Chromatin Immunoprecipitation; Coronary Artery Disease - metabolism; Efflux; Embryogenesis; Embryonic growth stage; Endothelium; Expansion; Gene expression; Gene Expression Regulation; Gene sequencing; Genomes; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hypercholesterolemia; Hypercholesterolemia - metabolism; Immunoprecipitation; Leukocytes; Lipoproteins; Progenitor cells; Proteins; Racemases and Epimerases - metabolism; Receptors, Notch - genetics; Ribonucleic acid; RNA; Sterol Regulatory Element Binding Protein 2 - metabolism; Transcription factors; Transposase; Zebrafish; Zebrafish Proteins - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aav1749

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.