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  • Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice.

Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice.

Nature communications (2017-07-27)
Xuan Jiang, John S Hawkins, Jerry Lee, Carlos O Lizama, Frank L Bos, Joan P Zape, Prajakta Ghatpande, Yongbo Peng, Justin Louie, Giorgio Lagna, Ann C Zovein, Akiko Hata
ABSTRACT

Hematopoietic stem and progenitor cells arise from the vascular endothelium of the dorsal aorta and subsequently switch niche to the fetal liver through unknown mechanisms. Here we report that vascular endothelium-specific deletion of mouse Drosha (Drosha cKO), an enzyme essential for microRNA biogenesis, leads to anemia and death. A similar number of hematopoietic stem and progenitor cells emerge from Drosha-deficient and control vascular endothelium, but Drosha cKO-derived hematopoietic stem and progenitor cells accumulate in the dorsal aorta and fail to colonize the fetal liver. Depletion of the let-7 family of microRNAs is a primary cause of this defect, as it leads to activation of leukotriene B4 signaling and induction of the α4β1 integrin cell adhesion complex in hematopoietic stem and progenitor cells. Inhibition of leukotriene B4 or integrin rescues maturation and migration of Drosha cKO hematopoietic stem and progenitor cells to the fetal liver, while it hampers hematopoiesis in wild-type animals. Our study uncovers a previously undefined role of innate leukotriene B4 signaling as a gatekeeper of the hematopoietic niche transition.Hematopoietic stem and progenitor cells are generated first from the vascular endothelium of the dorsal aorta and then the fetal liver but what regulates this switch is unknown. Here, the authors show that changing miRNA biogenesis and leukotriene B4 signaling in mice modulates this switch in the niche.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Integrin α4 Antibody, clone PS/2, clone PS/2, Chemicon®, from rat
Roche
In Situ Cell Death Detection Kit, Fluorescein, sufficient for ≤50 tests, suitable for detection