Acute inflammation induces acute megakaryopoiesis with impaired platelet production during fetal hematopoiesis

Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A methyltransferase METTL3 induces formation of double-stranded RNAs (dsRNAs) and activates acute inflammation during fetal hematopoiesis in mouse. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors but disrupts megakaryocyte maturation and platelet production. The inflammation and immune response activate the phosphorylation of STAT1 and IRF3, and upregulate downstream interferon-stimulated genes (ISGs). Inflammation inhibits the proliferation rate of hematopoietic progenitors and further skews the cell fate determination toward megakaryocytes rather than toward erythroid from megakaryocyte-erythroid progenitors (MEPs). Transcriptional-wide gene expression analysis identifies IGF1 as a major factor whose reduction is responsible for the inhibition of megakaryopoiesis and thrombopoiesis. Restoration of IGF1 with METTL3-deficient hematopoietic cells significantly increases megakaryocyte maturation. In summary, we elucidate that the loss of RNA m6A modification-induced acute inflammation activates acute megakaryopoiesis, but impairs its final maturation through the inhibition of IGF1 expression during fetal hematopoiesis.