期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 5, 页码 633-648出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141514
关键词
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资金
- US National Institute of Diabetes and Digestive and Kidney Diseases [R24-DK092760]
- National Heart, Lung, Blood Institute Progenitor Cell Biology Consortium [U01-HL100001]
- Alex's Lemonade Stand
- Doris Duke Medical Foundation
- American Heart Association
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA
- True North Therapeutics, Inc.
- Solasia
- KK
- Epizyme, Inc.
- Verastem, Inc.
- Ocata Therapeutics
- Raze, Inc.
- MPM Capital
- LLP
Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aortagonad- mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VE-cadherin(+) cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-tohematopoietic transition.
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