Multipotent stem cells give rise to mature specialized cells through a series of lineage-restricted differentiation events. During stem cell differentiation, fate decisions are often believed to be controlled by differential expression of lineage-specific transcription factors through cell-intrinsic noise, but cytokine receptor signals are also believed to play a crucial instructive role in addition to providing permissive proliferation and survival cues. Here, we present a minimal computational framework that integrates intrinsic and extrinsic regulatory processes implicated in cell differentiation. Our model highlights the potential importance of bidirectional interactions between cytokine receptors and transcription factors in conferring properties such as ultrasensitivity and multistability to differentiating cells. We have also explored how these interactions, coupled with transcriptional cross-antagonism, may influence the commitment of multipotent progenitors. Our simulations are in good agreement with recent experimental data, in which strong synergy is observed in the upregulation of both specific receptors and transcription factors along certain hematopoietic lineages, and may help to further elucidate how transcriptional priming may lead to a stable bipotent progenitor state.

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