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Science. 2019 Jan 31. pii: eaav1749. doi: 10.1126/science.aav1749. [Epub ahead of print]

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

Gu Q1, Yang X1, Lv J1,2, Zhang J1,3, Xia B1,2, Kim JD1, Wang R4,5, Xiong F4, Meng S1, Clements TP6, Tandon B6, Wagner DS6, Diaz MF7, Wenzel PL7, Miller YI8, Traver D9, Cooke JP1,10,11, Li W4,5, Zon LI12, Chen K13,2,10,11, Bai Y14, Fang L13,10,11,15.

Author information

1
Center for Cardiovascular Regeneration, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA.
2
Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA.
3
Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
4
Department of Biochemistry and Molecular Biology, UTHealth McGovern Medical School, University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA.
5
Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA.
6
Department of BioSciences, Rice University, Houston, TX 77005, USA.
7
Children's Regenerative Medicine Program, Department of Pediatric Surgery, Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
8
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
9
Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
10
Houston Methodist Institute for Academic Medicine, Houston Methodist Research Institute, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA.
11
Department of Cardiothoracic Surgeries, Weill Cornell Medical College, Cornell University, Ithaca, NY 10065, USA.
12
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
13
Center for Cardiovascular Regeneration, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA. lhfang@houstonmethodist.org kchen2@houstonmethodist.org baiyongping@csu.edu.cn.
14
Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China. lhfang@houstonmethodist.org kchen2@houstonmethodist.org baiyongping@csu.edu.cn.
15
Department of Obstetrics and Gynecology, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA.

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 pro-hematopoietic 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 ChIP-seq, RNA-seq, and ATAC-seq indicate that Srebp2 trans-regulates 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.

PMID:
30705153
DOI:
10.1126/science.aav1749

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