Regulatory feedback effects on tissue growth dynamics in a two-stage cell lineage model.

Identifying the mechanism of intercellular feedback regulation is critical for the basic understanding of tissue growth control in organisms. In this paper, we analyze a tissue growth model consisting of a single lineage of two cell types regulated by negative feedback signaling molecules that undergo spatial diffusion. By deriving the fixed points for the uniform steady states and carrying out linear stability analysis, phase diagrams are obtained analytically for arbitrary parameters of the model. Two different generic growth modes are found: blow-up growth and final-state controlled growth which are governed by the nontrivial fixed point and the trivial fixed point, respectively, and can be sensitively switched by varying the negative feedback regulation on the proliferation of the stem cells. Analytic expressions for the characteristic timescales for these two growth modes are also derived. Remarkably, the trivial and nontrivial uniform steady states can coexist and a sharp transition occurs in the bistable regime as the relevant parameters are varied. Furthermore, the bistable growth properties allows for the external control to switch between these two growth modes. In addition, the condition for an early accelerated growth followed by a retarded growth can be derived. These analytical results are further verified by numerical simulations and provide insights on the growth behavior of the tissue. Our results are also discussed in the light of possible realistic biological experiments and tissue growth control strategy. Furthermore, by external feedback control of the concentration of regulatory molecules, it is possible to achieve a desired growth mode, as demonstrated with an analysis of boosted growth, catch-up growth and the design for the target of a linear growth dynamic.