| Literature DB >> 30705153 |
Xiaojie Yang1, Jie Lv1,2, Jiaxiong Zhang1,3, Qilin Gu1, Bo Xia1,2, Jun-Dae Kim1, Ruoyu Wang4,5, Feng Xiong4, Shu Meng1, Thomas P Clements6, Bhavna Tandon6, Daniel S Wagner6, Miguel F Diaz7, Pamela L Wenzel7, Yury I Miller8, David Traver9, John P Cooke1,10,11, Wenbo Li4,5, Leonard I Zon12, Kaifu Chen13,2,10,11, Yongping Bai14, Longhou Fang13,10,11,15.
Abstract
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.Entities:
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Year: 2019 PMID： 30705153 PMCID： PMC6469354 DOI： 10.1126/science.aav1749
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728