The origin of hematopoietic cell type diversity.

The hematopoietic system remains robust with regards to extrinsic perturbations, in sharp contrast with the stochastic behavior of hematopoeitic stem cells (HSCs) at the single cell level, suggesting that stability may be achieved within a stem cell system that undergoes constant self-renewal, commitment to differentiation and generates cell type diversification. Converging evidence at the interface of cellular, molecular and numerical studies suggests that diversity is generated by the chaotic dynamics of transcription factor networks within a cell and of the combination of growth factors and cytokines in the environment, both involving cooperation and competition. Current evidence indicates that HSCs are primed for multilineage gene expression. A subtle shift in transcription factor dosage is sufficient to perturb this equilibrium and to drive lineage commitment that involves a resolution of complexity at the molecular level and a transition towards less chaotic behavior. This dynamical instability establishes a state of responsiveness to extrinsic signals. Evolutionary conserved environmental cues that drive pattern formation or migratory behavior during embryonic development operate in the adult to influence the decision between self-renewal and differentiation in HSCs, as exemplified by the role of Notch1, Wnt proteins, BMPs and VEGF. In contrast, a network of cytokines uniquely present in mammalians influences later developmental stages, from progenitors with more restricted potentials (tri-, bi- or unipotent) to mature functional cells. These cytokines have co-opted the ancient Jak-STAT pathway but also appear to trigger lineage-affiliated transcription factors, thus linking environmental signaling to cell fate decisions.