Tahereh Derakhshan, MD
Postdoctoral Research Fellow
T. Derakhshan, E. Hollers, T. Laidlaw, J.A. Boyce, D.F. Dwyer
Research Category: Allergy, Immunology, Inflammation, and Infectious Diseases
Mast cells (MCs) are central regulators of type 2 inflammatory diseases, including asthma and nasal polyposis, producing factors that elicit bronchoconstriction and leukocyte infiltration. MCs develop from circulating progenitors that mature in peripheral tissues under the regulation of microenvironmental factors. In nasal polyposis, MC expansion is partially driven by the proliferation of transcriptionally immature MCs within the subepithelium that correlates with disease severity. Thus, we hypothesized that structural cells within the subepithelium direct the proliferation of immature MCs. Using single-cell RNA sequencing, we identified a population of CD34+ cells expressing MC-associated transcripts (TPSAB1, HDC, FCER1A) present in both the nasal polyp and peripheral blood, and characterized by a discrete cell surface protein expression profile (CD71, CD131, CD33, CD203c). Following flow cytometric isolation, these MC progenitors had limited proliferation capacity in monoculture, but robustly proliferated when co-cultured with airway fibroblasts. Fibroblast co-culture further enhanced intracellular chymase levels and cell surface expression of the innate activating receptor MRGPRX2. Thus, our findings suggest a central role for fibroblasts in both driving MC expansion and shaping the subepithelial MC phenotype.
Mast cells (MCs) are immune cells that expand in the airways during allergic disease and produce factors that drive tissue inflammation. However, the mechanism underlying MC expansion remains unclear. Here, we identified MC precursors present in the circulation and nasal polyp tissue and conducted a comprehensive analysis of the genes and surface proteins expressed by these cells. When we cultured these cells with fibroblasts, structural cells found beneath the surface of airway tissue, we observed a substantial enhancement in MC precursor proliferation potential. Thus, the interaction between fibroblasts and MC precursors plays a significant role in MC expansion.