Cytokines regulate development of human mast cells from hematopoietic progenitors

Abstract

Combination of stem cell factor (SCF) and interleukin-6 (IL-6) significantly promoted proliferation of human mast cells from cord blood CD34+ cells. Most of the cells, cultured in the presence of SCF and IL-6 for 10 weeks, expressed c-kit and contained a significant amount of histamine and tryptase and a low amount of chymase. Both tryptase-positive chymase-negative mast cells (MC(T)) and tryptase-positive chymase-positive mast cells (MC(TC)) were found in the same colony derived from a single cord blood CD34+ cell, suggesting that MC(T) and MC(TC) develop from common precursor cells. Single-cell culture of CD34+ cells revealed that committed mast cell progenitors are included in CD34+CD38+HLA-DR- cells. IL-4 significantly enhanced high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) alpha-chain messenger RNA expression and induced FcepsilonRI on SCF-dependent cord blood-derived human mast cells, resulting in high histamine-releasing activity upon cross-linking of FcepsilonRI. Another factor that up-regulated FcepsilonRI was IgE, and a combination of IL-4 and IgE markedly augmented FcepsilonRI expression on the mast cells. IL-4 and IgE may enhance FcepsilonRI expression by distinct mechanisms; IL-4 promotes FcepsilonRI alpha-chain gene transcription and thus increases alpha-chain protein synthesis in the cells, whereas the binding of IgE may anchor the FcepsilonRI on the cell surface, resulting in suppression of internalization of FcepsilonRI. Mast cells are progeny of hematopoietic stem cells. Recent discovery of a xenotransplantation model revealed that human hematopoietic stem cells can proliferate and differentiate into mature mast cells in the mouse skin 3 months after transplantation of human cord blood CD34+ cells, suggesting that this model may pave the way to clarification of the functions of human mast cells in vivo.