A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

Cells do not function in isolation. Arguably, every cell fate decision occurs in response to environmental signals. In many cases cell-cell communication alters the dynamics of a cell’s internal gene regulatory network to initiate cell fate transitions, yet models rarely take this into account. Here we develop a multiscale perspective to study the granulocyte-monocyte vs. megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network, a classical example of a bistable cell fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell fate decision-making system.