The paracrine factor myeloid derived growth factor regulates the inflammatory fate and motility of human induced pluripotent stem cell-derived neutrophils.

Neutrophils are necessary for host defense but also contribute to tissue damage. Understanding the molecular mechanisms that govern human neutrophil development and fate is critical for developing interventions for treating and preventing human disease. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are genetically tractable and provide a robust source of neutrophils to dissect molecular regulation and for potential use in infusion therapies. Here, we show that deletion of the paracrine factor myeloid-derived growth factor (MYDGF) in human iPSCs results in the development of iNeutrophils with improved zymosan-induced reactive oxygen species generation and antimicrobial functions. MYDGF-deficient iNeutrophils showed improved transendothelial migration to microbes in organotypic models and motility in confined microchannels. We identify MYDGF as a new endogenous inhibitor of cytosolic calcium dynamics that suppresses neutrophil inflammatory activity. Our findings show that MYDGF mediates neutrophil-to-neutrophil communication during migration through a paracrine mechanism. Since MYDGF-deficient iNeutrophils show improved effector and antimicrobial function, these cells may improve future therapeutic use of iNeutrophils for infusion therapies. Finally, soluble MYDGF provides an attractive strategy to limit chronic neutrophil-mediated inflammation and tissue damage.