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

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 and Akiko Hata ()
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Xuan Jiang: University of California, San Francisco
John S. Hawkins: University of California, San Francisco
Jerry Lee: University of California, San Francisco
Carlos O. Lizama: University of California, San Francisco
Frank L. Bos: University of California, San Francisco
Joan P. Zape: University of California, San Francisco
Prajakta Ghatpande: University of California, San Francisco
Yongbo Peng: University of California, San Francisco
Justin Louie: University of California, San Francisco
Giorgio Lagna: University of California, San Francisco
Ann C. Zovein: University of California, San Francisco
Akiko Hata: University of California, San Francisco

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00137-y

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