{"title":"Acute inflammation induces acute megakaryopoiesis with impaired platelet production during fetal hematopoiesis.","authors":"Xiaojie Hu, Yirui He, Shengwei Li, Yue Jiang, Renjie Yu, Yi Wu, Xiaoying Fu, Yuanbin Song, Changdong Lin, Jiejun Shi, Hua-Bing Li, Yimeng Gao","doi":"10.1242/dev.204226","DOIUrl":null,"url":null,"abstract":"<p><p>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. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors (MkP) 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 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 increase 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.</p>","PeriodicalId":11375,"journal":{"name":"Development","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Development","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1242/dev.204226","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors (MkP) 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 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 increase 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.
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Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community.
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To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.
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