miRNA-based mechanism for the commitment of multipotent progenitors to a single cellular fate

When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate and blocking differentiation along alternative routes. We herein present a mechanism whereby such unequivocal commitment is achieved, based on microRNA (miRNA)-dependent repression of an alternative cell fate. We show that the commitment of monocyte RAW264.7 progenitors to active macrophage differentiation involves rapid up-regulation of miR-155 expression, which leads to the suppression of the alternative pathway, namely RANK ligand-induced osteoclastogenesis, by repressing the expression of MITF, a transcription factor essential for osteoclast differentiation. A temporal asymmetry, whereby miR-155 expression precedes and overrides the activation of the osteoclast transcriptional program, provides the means for coherent macrophage differentiation, even in the presence of osteoclastogenic signals. Based on these findings, we propose that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation.