A novel approach for studying mast cell–driven disorders: Mast cells derived from induced pluripotent stem cells

Background Mast cells (MCs) are considered the main effectors in allergic reactions and well known for their contribution to the pathogenesis of various inflammatory diseases, urticaria, and mastocytosis. To study their functions in vitro, human primary MCs are isolated directly from several tissues or differentiated from hematopoietic progenitors. However, these techniques bear several disadvantages and challenges including low proliferation capacity, donor-dependent heterogeneity, and the lack of a continuous cell source. Objective To address this, we developed a novel strategy for the rapid and efficient differentiation of MCs from human-induced pluripotent stem cells (hiPSCs). Methods A 4-step protocol for the generation of hiPSC-derived MCs, based on the use of 3 hiPSC lines, was established and validated by comparison with human skin MCs and peripheral hematopoietic stem cell–derived MCs. Results hiPSC-MCs share phenotypic and functional characteristics of human skin MCs and peripheral hematopoietic stem cell–derived MCs. They display stable expression of the MC-associated receptors CD117, FcεRIα, and Mas-related G protein–coupled receptor X2 and degranulate in response to IgE/anti-IgE and substance P. Conclusions This novel hiPSC-based approach provides a sustainable and homogeneous source for a rapid and highly productive generation of phenotypically mature, functional MCs, and its principle allows for the investigation of disease- and patient-specific MC populations. Mast cells (MCs) are considered the main effectors in allergic reactions and well known for their contribution to the pathogenesis of various inflammatory diseases, urticaria, and mastocytosis. To study their functions in vitro, human primary MCs are isolated directly from several tissues or differentiated from hematopoietic progenitors. However, these techniques bear several disadvantages and challenges including low proliferation capacity, donor-dependent heterogeneity, and the lack of a continuous cell source. To address this, we developed a novel strategy for the rapid and efficient differentiation of MCs from human-induced pluripotent stem cells (hiPSCs). A 4-step protocol for the generation of hiPSC-derived MCs, based on the use of 3 hiPSC lines, was established and validated by comparison with human skin MCs and peripheral hematopoietic stem cell–derived MCs. hiPSC-MCs share phenotypic and functional characteristics of human skin MCs and peripheral hematopoietic stem cell–derived MCs. They display stable expression of the MC-associated receptors CD117, FcεRIα, and Mas-related G protein–coupled receptor X2 and degranulate in response to IgE/anti-IgE and substance P. This novel hiPSC-based approach provides a sustainable and homogeneous source for a rapid and highly productive generation of phenotypically mature, functional MCs, and its principle allows for the investigation of disease- and patient-specific MC populations.