KIT D816V mast cells derived from induced pluripotent stem cells recapitulate systemic mastocytosis transcriptional profile

Mast cells (MC) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MC occur in low abundance which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells of the body and established a robust protocol for human iPS cell differentiation towards MC. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MC that recapitulate SM disease features: increased number of MC, abnormal maturation kinetics and activated phenotype, CD2 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MC are a reliable and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics. Overall design: Comparative gene expression profiling analysis of RNA-seq data for KIT D816V mast cells and WT mast cells