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

Abstract

Mast cell accumulation is a hallmark of a number of diseases including allergic asthma and systemic mastocytosis. IgE-mediated crosslinking of the FcϵRI 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 there are still controversies about the identity of the mast cell progenitor, i.e., whether FcϵRI expression appears during the hematopoietic progenitor stage or in maturing mast cells. Here, we used single-cell transcriptomics to reveal a temporal association between the appearance of FcϵRI and the mast cell gene signature in CD34+ hematopoietic progenitors. In agreement with these data, the FcϵRI+ 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 mast cell progenitor development. Culture assays showed that IL-3 and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust FcϵRI downregulation. Taken together, we have demonstrated that FcϵRI appears during the hematopoietic progenitor stage of mast cell differentiation and that external stimuli may regulate the FcϵRI expression. Thus, the results resolve the controversy regarding the appearance of FcϵRI during mast cell development.

A time and single-cell resolved model of hematopoiesis

“…Similarly slow is the plasmacytoid dendritic cell (cluster 13, pDCs) differentiation through the lymphoid cluster 14 and myeloid clusters 6 and 16. The emergence of mast cell, basophil and eosinophil progenitors in the adult bone marrow is unclear (Hamey et al, 2021; Wu et al, 2022). Our results reveal that basophil and mast cell progenitors (cluster 12) are continuously generated and originate mostly by a transition from cluster 2.…”