Resolution of a human mast cell development conundrum

Abstract

The study of cytokine requirements for development of a granulated human mast cell (MC) from circulating bone marrow (BM)-derived progenitors (MCp) by Dahlin et al, 1 in this issue of Blood, identifies an interleukin-3 (IL-3)-dependent viability and maturation stage distinct from the subsequent stem cell factor (SCF)- induced secretory granule (SG) mature stage (see figure). IL-3 alone was known to be insufficient for development of identifiable human MC, and the consensus opinion for their in vitro generation used the cytokine combination of SCF, IL-6, and IL-3.2 Dahlin et al noted that MCp, identified as CD45int, CD341, SSClo, Lin2, CD117int/hi (Kit), and FceR11 cells, were present in low numbers in normal subjects. Others had observed that patients treated with imatinib, which blocks membrane protein kinases including the KIT receptor, became MC deficient.3 When Dahlin et al found that MCp were not reduced in patients treated with imatinib, they concluded that SCF was not needed for MCp development. They next cultured MCp with IL-3 1 IL-6, noting prolonged survival with early signs of maturation, and they termed these cultured cells pre-MC. The IL-3 1 IL-6-induced development of pre-MC from MCp was associated with downregulation of CD34 and b7 integrin and appearance of SG metachromasia and tryptase immunodetection. This conversion occurred even in the presence of imatinib or anti-SCF, establishing that Kit signaling played no role in this early maturation of MCp to pre-MC. Whereas IL-3 alone promoted survival of IL-3 1 IL-6-generated pre-MC, IL-6 had no effect and was not further assessed. Thus, the authors used in vivo data to highlight the Kit independence of MCp and then characterized a distinct MCp-derived intermediate stage of maturation, pre-MC, on the path to full SCF-mediated maturation in culture.