Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production

• Published in: Developmental cell 2020-10, Vol.55 (2), p.133-149.e6
• Main Authors: Frame, Jenna M., Kubaczka, Caroline, Long, Timothy L., Esain, Virginie, Soto, Rebecca A., Hachimi, Mariam, Jing, Ran, Shwartz, Arkadi, Goessling, Wolfram, Daley, George Q., North, Trista E.
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Core Binding Factor Alpha 2 Subunit - metabolism; Embryo, Nonmammalian - metabolism; Embryonic Development - physiology; Embryonic Stem Cells - metabolism; endothelial-to-hematopoietic transition (EHT); Hematopoiesis - physiology; hematopoietic stem cell (HSC); Hematopoietic Stem Cells - metabolism; Humans; IL1β; Induced Pluripotent Stem Cells - metabolism; inflammasome; Inflammasomes - metabolism; inflammation; iPSC; Nlrp3; zebrafish; Zebrafish - embryology
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.07.015

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. [Display omitted] •Developmental metabolic shifts prime inflammasome-associated il1b expression in vivo•Loss of inflammasome function inhibits HSPC production in the zebrafish embryo•IL1β+ macrophages promote the production of Il1rl1+ HSPCs via inflammasome action in vivo•Inflammasome activation enhances HSPC production in human hemogenic cultures Frame et al. identify an integral role for the inflammasome in stimulating de novo production of zebrafish and human hematopoietic stem and progenitor cells (HSPCs). Inflammasome-associated IL1β signaling is induced in vivo by developmental metabolic cues and relayed from primitive macrophages to hemogenic endothelium to promote embryonic HSPC formation.