Neutrophils are the most abundant leukocyte in the human immune system and act as first responders to infection. While they are plentiful, their metabolism and mechanisms of effector function regulation is not well understood because primary human neutrophils are short-lived and genetically intractable. Therefore, an alternative model system is needed. Here, we demonstrate the utility of using human iPSC derived neutrophils (iNeutrophils) to study their function. Transcription factor GATA1 is known to have a role in leukocyte maturation. Here we show that GATA1 knockout (GATA1 KO) iNeutrophils are phenotypically similar to primary human neutrophils based on single-cell RNAseq and surface marker expression. We propose that the GATA1 KO line provides a genetically tractable model to study neutrophil metabolism and its regulation of effector function in vitro. Early metabolomics data show an increase of pentose phosphate pathway intermediates in our GATA1 KO iNeutrophils with activation – a hallmark seen in activated primary neutrophils. This metabolic shift plays a role in enhanced antimicrobial activity. Accordingly, we demonstrate that GATA1 KO iNeutrophils produce higher levels of reactive oxygen species (ROS) and inhibit growth of the fungus Aspergillus fumigatus similar to primary neutrophils. Therefore, we suggest that the GATA1 KO iNeutrophil line has the potential to serve as an effective tool to understand neutrophil metabolism and host defense functions in vitro.
GATA1-deficient iPSC-derived neutrophils show altered metabolism and effector functions
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Poster
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Date: May 4 Presentation Time: 11:30 AM to 12:45 PM Room: Exhibit Hall F1