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

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.

Defining murine organogenesis at single-cell resolution reveals a role for the leukotriene pathway in regulating blood progenitor formation

“…Unlike the previously identified transcriptional regulators of EHT such as Runx1 or Gfi1 / Gfi1b 28 , the leukotriene pathway will be easier to exploit in a translational setting because of the ready availability of small molecule agonists and antagonists. Leukotrienes are produced in a multi-step process from arachidonic acid, which can be metabolised into a number of distinct functionally active molecules, all with their own receptors and spectrum of biological activities, including the fine-tuning of haematopoietic stem cell activity at the time of their first emergence in the aorta-gonad-mesonephros region at E11.5 29 . Of note, the arachidonic acid derivatives prostaglandin and epoxyeicosatrienoic acid have been identified in small molecule screens for compounds that can amplify blood stem and progenitor cells 30 , 31 , and have already entered clinical trials to enhance blood stem cell transplantation 32 .…”

Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

“…S4A), demonstrating efficient deletion of Drosha in endothelial cells. Vasculogenesis and angiogenesis appeared superficially normal in Drosha cKO EC embryos; however, all cKO EC embryos died around E14.5 to E15.5 due to a hematopoiesis defect (27). Immunofluorescence staining of the endothelial marker CD31 showed that branching of blood vessels was reduced by 20% in the yolk sacs of cKO EC embryos at E13.5 compared to those of control embryos (fig.…”

“…For example, inactivation of endothelial cell–specific miR-126 is sufficient to cause ISV defects similar to those observed in Drosha morphants in zebrafish (33). However, miR-126 biogenesis is independent of Drosha (33), and the abundance of miR-126 is not affected in Drosha morphants or Drosha cKO EC mice (27). Thus, future studies are necessary to identify endothelial cell–specific miRNAs that are essential for the vascular development and homeostasis.…”

Epigenetic and Epitranscriptomic Factors Make a Mark on Hematopoietic Stem Cell Development

“…miRNAs regulate m 6 A levels by directing METTL3 binding to mRNAs in a sequence-dependent and AGO2-independent manner. In addition to miR-223, miR-142 and let-7 are also required for HSC formation [61, 62], and numerous miRNAs are differentially expressed during EHT in mouse [63], suggesting that this class of small RNAs will likely have a central role in modulating EHT gene expression levels, be it through epigenetic, epitranscriptomic or posttranscriptional gene regulation.…”