RRC ID 66011
Author Frame JM, Kubaczka C, Long TL, Esain V, Soto RA, Hachimi M, Jing R, Shwartz A, Goessling W, Daley GQ, North TE.
Title Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production.
Journal Dev Cell
Abstract Embryonic hematopoietic stem and progenitor cells (HSPCs) robustly proliferate while maintaining multilineage potential in vivo; however, an incomplete understanding of spatiotemporal cues governing their generation has impeded robust production from human induced pluripotent stem cells (iPSCs) in vitro. Using the zebrafish model, we demonstrate that NLRP3 inflammasome-mediated interleukin-1-beta (IL1β) signaling drives HSPC production in response to metabolic activity. Genetic induction of active IL1β or pharmacologic inflammasome stimulation increased HSPC number as assessed by in situ hybridization for runx1/cmyb and flow cytometry. Loss of inflammasome components, including il1b, reduced CD41+ HSPCs and prevented their expansion in response to metabolic cues. Cell ablation studies indicated that macrophages were essential for initial inflammasome stimulation of Il1rl1+ HSPCs. Significantly, in human iPSC-derived hemogenic precursors, transient inflammasome stimulation increased multilineage hematopoietic colony-forming units and T cell progenitors. This work establishes the inflammasome as a conserved metabolic sensor that expands HSPC production in vivo and in vitro.
Volume 55(2)
Pages 133-149.e6
Published 2020-10-26
DOI 10.1016/j.devcel.2020.07.015
PII S1534-5807(20)30589-X
PMID 32810442
PMC PMC8008739
MeSH Animals Cell Differentiation / physiology Core Binding Factor Alpha 2 Subunit / metabolism Embryo, Nonmammalian / metabolism Embryonic Development / physiology Embryonic Stem Cells / metabolism* Hematopoiesis / physiology Hematopoietic Stem Cells / metabolism* Humans Induced Pluripotent Stem Cells / metabolism* Inflammasomes / metabolism* Zebrafish / embryology
IF 10.092
Zebrafish Tg(EF1α:mAG-zGem(1/100)) rw0410h