Spatial Dynamics of Feedback and Feedforward Regulation in Cell Lineages

Feedback mechanisms within cell lineages are thought to be important for maintaining tissue homeostasis. Mathematical models that assume well-mixed cell populations, together with experimental data, have suggested that negative feedback from differentiated cells on the stem cell self-renewal probability can maintain a stable equilibrium and hence homeostasis. Cell lineage dynamics, however, are characterized by spatial structure, which can lead to different properties. Here, we investigate these dynamics using spatially explicit computational models, including cell division, differentiation, death, and migration / diffusion processes. According to these models, the negative feedback loop on stem cell self-renewal fails to maintain homeostasis, both under the assumption of strong spatial restrictions and fast migration / diffusion. Although homeostasis cannot be maintained, this feedback can regulate cell density and promote the formation of spatial structures in the model. Tissue homeostasis, however, can be achieved if spatially restricted negative feedback on self-renewal is combined with an experimentally documented spatial feedforward loop, in which stem cells regulate the fate of transit amplifying cells. This indicates that the dynamics of feedback regulation in tissue cell lineages are more complex than previously thought, and that combinations of spatially explicit control mechanisms are likely instrumental.