Myeloid Derived Growth Factor is an endogenous, paracrine regulator of neutrophil activation and confined motility

Neutrophils are necessary for host defense but also contribute to tissue damage. Therefore, it is important to understand mechanisms that limit neutrophil-driven inflammation. We previously reported that myeloid derived growth factor (MYDGF) restricts neutrophil inflammation in zebrafish. However, the mechanism of MYDGF's effects remain unknown. Here, we generated human induced pluripotent stem cells (iPSCs)-derived neutrophils (iNeutrophils) that are deficient in MYDGF to identify neutrophil intrinsic roles for MYDGF. Depletion of MYDGF results in iNeutrophils that have increased ROS production, confined motility and antimicrobial efficacy. Secreted MYDGF was sufficient to rescue motility in a MYDGF-deficient iNeutrophil line and modulate primary human neutrophil behavior, suggesting neutrophil paracrine signaling. MYDGF-KO iNeutrophils exhibit increased calcium flux during confined motility in response to fMLP. Taken together, our data identify MYDGF as an endogenous negative regulator of neutrophil inflammatory function and cell-cell communication. Overall design: Wildtype and MYDGF-/- bone marrow-derived human iPSCs were differentiated into iNeutrophils and collected at Day 7 for single-cell RNA profiling.