Fceri+ multipotent progenitors drive mast cell-mediated allergic responses at mucosal sites - allergic diseases of mucosal surfaces have continued to increase significantly, yet IT remains unclear why…

The National Institute of Allergy and Infectious Diseases awarded a cooperative agreement totaling $564,548 to the Regents of the University of Michigan on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds research into how bone-marrow multipotent progenitors bearing the FcεRI receptor drive mast-cell–mediated allergic responses at mucosal sites. The project addresses the gap between current therapies that target downstream mast-cell effectors and the upstream cellular mechanisms that seed pathogenic mast-cell pools central to chronic allergic disease including atopic dermatitis, asthma, and food allergy. The research will define FcεRI-positive multipotent progenitor populations across steady-state and allergen-challenged lung and gut tissues using optimized single-cell genomics and flow-cytometry validation; establish lineage commitment and sufficiency by comparing FcεRI-positive and FcεRI-negative progenitor differentiation in vitro and their capacity to reconstitute mucosal mast cells and restore allergic responses following adoptive transfer into mast-cell–deficient hosts; and generate human FcεRI progenitors from induced pluripotent stem cells to establish their relevance using humanized allergic models with single-cell analytics to identify potential modulators and predictive biomarkers.

Work is performed at Ann Arbor, Michigan. The period of performance runs through July 31, 2031.

Fceri+ multipotent progenitors drive mast cell-mediated allergic responses at mucosal sites - allergic diseases of mucosal surfaces have continued to increase significantly, yet IT remains unclear why some individuals develop persistent allergy. Atopic diseases, including atopic dermatitis, asthma, and food allergy, affect >50 million americans and ~20% of the global population. Current therapies largely target downstream mast-cell (MC) effectors rather than the upstream cellular programs that seed pathogenic MC pools that are central to allergic disease. Our preliminary data identify a previously unappreciated fcεriα-positive (fcεri⁺) subset within bone-marrow multipotent progenitors (MPP1/MPP3) that expands with allergic sensitization, appears MC-lineage-restricted, and is detectable in bone marrow, blood, and gastrointestinal tissues, suggesting that allergen sensing is embedded at the progenitor level. Our central hypothesis is that allergen-induced responses reprogram ML progenitors via cytokine and cellular cues, driving tissue-specific differentiation programs that lead to chronic allergic inflammation. We will (aim 1) define fcεri⁺ MPP populations across steady-state and allergen- challenged lung and GUT using an optimized 132-antibody cite-SEQ panel with flow-cytometry validation, and reconstruct trajectories from fcεri⁺ mpps to tissue MCS via pseudotime and sctriangulate to pinpoint fate-commitment checkpoints; (aim 2) establish lineage commitment and sufficiency by comparing fcεri⁺ versus fcεri⁻ MPP differentiation in vitro and their capacity to reconstitute mucosal MCS and restore allergic responses following adoptive transfer into MC- deficient hosts; and (aim 3) generate human fcεri⁺ mpps from ipscs and establish their relevance using NSG-SGM3 humanized allergic models with single-cell analytics to potential identify modulators and predictive biomarkers. Significance: this work reframes allergic disease as a disorder initiated upstream at the progenitor level, to not merely suppress, but opportunities to prevent effector responses. This integrated proposal will provide an atlas of fcεri⁺ progenitors, mechanistic verification of MC-lineage restriction and disease sufficiency, and human-validated mechanistic targets to potentially control atopic disease.