Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 8;363(6431):1085-1088.
doi: 10.1126/science.aav1749. Epub 2019 Jan 31.

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

Qilin Gu  1 , Xiaojie Yang #  1 , Jie Lv #  1   2 , Jiaxiong Zhang #  1   3 , Bo Xia  1   2 , Jun-Dae Kim  1 , Ruoyu Wang  4   5 , Feng Xiong  4 , Shu Meng  1 , Thomas P Clements  6 , Bhavna Tandon  6 , Daniel S Wagner  6 , Miguel F Diaz  7 , Pamela L Wenzel  7 , Yury I Miller  8 , David Traver  9 , John P Cooke  1   10   11 , Wenbo Li  4   5 , Leonard I Zon  12 , Kaifu Chen  13   2   10   11 , Yongping Bai  14 , Longhou Fang  13   10   11   15
Affiliations

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

Qilin Gu et al. Science. .

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Y.I.M. and L.F. are inventors on patent application (US20160115211A1 and WO2014193822A1). L.Z. holds stock and is a consultant and on the SAB of FATE Therapeutics, Scholar Rock, Camp4 and Celularity.

Figures

Fig. 1.
Fig. 1.. Effect of Aibp2 and cholesterol on HSC emergence.
A. Whole-mount in situ hybridization (WISH) analysis of runx1, cmyb, rag1, and efnb2a expression. B. HSC emergence in control or Aibp2-deficient cmyb:GFP; kdrl:mCherry zebrafish. C. WISH analysis of runx1 in animals with the indicated treatments. Ethanol: EtOH. Arrowheads in A indicate DA or thymus, and in B show cmyb+kdrl+ HSCs. Scale bar, 100 μm.
Fig. 2.
Fig. 2.. Effect of Aibp2 on Srebp2 activity in ECs.
A. DNA constructs used to make the transgenic zebrafish with heat shock-induced Aibp2 expression. SS: secretion signal. B-C. qRT-PCR analyses of srebf1 and srebf2 in the AGM regions of Aibp2 overexpression (B) or knockdown zebrafish (C). D. Immunoblots of Srebp2 in HUVECs incubated with or without AIBP/HDL3 (μg/ml) for 4 hours. **, p<0.01. P: Srebp2 precursor; N: nuclear Srebp2.
Fig. 3.
Fig. 3.. Effect of Srebp2 on HSC emergence.
A. WISH analysis of the indicated genes in WT or srebf2−/− zebrafish. B and C. WISH analysis of runx1 expression in the DA. nSrebp2 OE: nuclear Srebp2 overexpression.
Fig. 4.
Fig. 4.. Effect of AIBP-regulated Srebp2 activity on Notch signaling.
A and B. WISH analysis of notch1b and runx1. The numerator indicates number of zebrafish with the representative phenotype, and denominator indicates the total number of animals assessed. C. Srebp2 binding motif enrichment in differentially expressed gene groups. TSS: translation start site. D. Immunoblotting of SREBP2 and NOTCH1 in the HSPCs isolated from low LDL-C (1.826 ± 0.089 mM; n=5) and high LDL-C (4.796 ± 0.454 mM; n=5) subjects. LAMIN A/C serves as the loading control. E. Working model. Bilateral cholesterol transport occurs between the ER and plasma membrane. AIBP-accelerated cholesterol efflux to HDL or hypercholesterolemia activates Srebp2, which transactivates Notch for hematopoiesis.
See this image and copyright information in PMC

Comment in

References

    1. Bertrand JY et al., Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111 (2010). - PMC - PubMed
    1. Boisset JC et al., In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010). - PubMed
    1. Kissa K, Herbomel P, Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010). - PubMed
    1. Nguyen PD et al., Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1. Nature 512, 314–318 (2014). - PubMed
    1. Fang L et al., Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 498, 118–122 (2013). - PMC - PubMed

Publication types

MeSH terms