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

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 Traver; John P. Cooke; Wenbo Li; Leonard I. Zon; Kaifu Chen; Yongping Bai; Longhou Fang

doi:10.1126/science.aav1749

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

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 Traver, John P. Cooke, Wenbo Li, Leonard I. Zon, Kaifu ChenYongping Bai, Longhou Fang

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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.

Original language	English (US)
Pages (from-to)	eaav1749
Journal	Science
DOIs	https://doi.org/10.1126/science.aav1749
State	Published - Mar 8 2019

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10.1126/science.aav1749

http://science.sciencemag.org/content/early/2019/01/30/science.aav1749.abstract

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Gu, Q., Yang, X., Lv, J., Zhang, J., Xia, B., Kim, J. D., Wang, R., Xiong, F., Meng, S., Clements, T. P., Tandon, B., Wagner, D. S., Diaz, M. F., Wenzel, P. L., Miller, Y. I., Traver, D., Cooke, J. P., Li, W., Zon, L. I., ... Fang, L. (2019). AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science, eaav1749. https://doi.org/10.1126/science.aav1749

Gu, Q, Yang, X, Lv, J, Zhang, J, Xia, B, Kim, JD, Wang, R, Xiong, F, Meng, S, Clements, TP, Tandon, B, Wagner, DS, Diaz, MF, Wenzel, PL, Miller, YI, Traver, D, Cooke, JP, Li, W, Zon, LI, Chen, K, Bai, Y & Fang, L 2019, 'AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate', Science, pp. eaav1749. https://doi.org/10.1126/science.aav1749

@article{1b10a73a65024c1a887c4ce98685e1e7,

title = "AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate",

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.",

author = "Qilin Gu and Xiaojie Yang and Jie Lv and Jiaxiong Zhang and Bo Xia and Kim, {Jun Dae} and Ruoyu Wang and Feng Xiong and Shu Meng and Clements, {Thomas P.} and Bhavna Tandon and Wagner, {Daniel S.} and Diaz, {Miguel F.} and Wenzel, {Pamela L.} and Miller, {Yury I.} and David Traver and Cooke, {John P.} and Wenbo Li and Zon, {Leonard I.} and Kaifu Chen and Yongping Bai and Longhou Fang",

year = "2019",

month = mar,

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doi = "10.1126/science.aav1749",

language = "English (US)",

pages = "eaav1749",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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T1 - AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate

AU - Gu, Qilin

AU - Yang, Xiaojie

AU - Lv, Jie

AU - Zhang, Jiaxiong

AU - Xia, Bo

AU - Kim, Jun Dae

AU - Wang, Ruoyu

AU - Xiong, Feng

AU - Meng, Shu

AU - Clements, Thomas P.

AU - Tandon, Bhavna

AU - Wagner, Daniel S.

AU - Diaz, Miguel F.

AU - Wenzel, Pamela L.

AU - Miller, Yury I.

AU - Traver, David

AU - Cooke, John P.

AU - Li, Wenbo

AU - Zon, Leonard I.

AU - Chen, Kaifu

AU - Bai, Yongping

AU - Fang, Longhou

PY - 2019/3/8

Y1 - 2019/3/8

N2 - 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.

AB - 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.

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SN - 0036-8075

SP - eaav1749

JO - Science

JF - Science

ER -

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

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