Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors

Mast cell accumulation is a hallmark of a number of diseases, including allergic asthma and systemic mastocytosis. Immunoglobulin E-mediated crosslinking of the Fc epsilon RI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages, and controversies remain about whether Fc epsilon RI expression appears during the mast cell progenitor stage or during terminal mast cell maturation. Here, we used single-cell transcriptomics analysis to reveal a temporal association between the appearance of Fc epsilon RI and the mast cell gene signature in CD341 hematopoietic progenitors in adult peripheral blood. In agreement with these data, the Fc epsilon RI+ hematopoietic progenitors formed morphologically, phenotypically, and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating development of mast cell progenitors. Culture assays showed that interleukin-3 (IL-3) and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust Fc epsilon RI downregulation. Taken together, we showed that FceRI expression appears at the progenitor stage of mast cell differentiation in peripheral blood. We also showed that external stimuli regulate Fc epsilon RI expression of mast cell progenitors, providing a possible explanation for the variable Fc epsilon RI expression levels during mast cell development.