Integration of cytokine and transcription factor signals in hematopoietic stem cell commitment

In the predominant model of hematopoietic stem cell differentiation lineage commitment is thought to be initiated by stochastic variation in the balance of lineage determining transcription factors, whereas cytokines have been seen in a purely permissive role of stimulating selective survival and proliferation of the down stream progeny. Recent observations, however, indicate that cytokines can also directly instruct cell fate change in uncommitted stem and progenitor cells by activating lineage determining transcription factors. We review the historic and recent evidence for instructive cytokine signaling and propose a model that integrates cytokine signaling and transcription factor activity in the initial decision making process, where the sensitivity to external instructive signals can be modulated by internal threshold setters. In contrast to a rigid stochastic explanation of lineage commitment this view allows for receptiveness of the hematopoietic stem cell to its environment and exposes lineage commitment as dependent on both instructive signals and cell intrinsically controlled sensitivity to external cues.