Abstract
The lack of understanding of stem cell differentiation and proliferation is a fundamental problem in developmental biology. Although gene regulatory networks (GRNs) for stem cell differentiation have been partially identified, the nature of differentiation dynamics and their regulation leading to robust development remain unclear. Herein, using a dynamical system modeling cell approach, we performed simulations of the developmental process using all possible GRNs with a few genes, and screened GRNs that could generate cell type diversity through cell-cell interactions. We found that model stem cells that both proliferated and differentiated always exhibited oscillatory expression dynamics, and the differentiation frequency of such stem cells was regulated, resulting in a robust number distribution. Moreover, we uncovered the common regulatory motifs for stem cell differentiation, in which a combination of regulatory motifs that generated oscillatory expression dynamics and stabilized distinct cellular states played an essential role. These findings may explain the recently observed heterogeneity and dynamic equilibrium in cellular states of stem cells, and can be used to predict regulatory networks responsible for differentiation in stem cell systems.
Highlights
Differentiation of multipotent stem cells to lineage-specific cells is one of the remarkable phenomena in developmental biology
Model setup We studied protein expression dynamics represented by the change in the concentration of proteinsp(i,t), for i~1,2, Á Á Á,k at time t
We presented the dynamic differentiation process of stem cells, in which the transition between cellular attractors is caused by dynamical instability arising from cell-cell interactions
Summary
Differentiation of multipotent stem cells to lineage-specific cells is one of the remarkable phenomena in developmental biology. Stem cells are defined as cells with the potential to both proliferate and differentiate into other cell types [1,2,3,4] This ability of cells (or their ‘‘stemness’’) is remarkable, since the cellular state must satisfy 2 conflicting properties: stability for proliferation and plasticity for differentiation. Such stemness is successively lost as the process of cell differentiation progresses during development. During this process, each cell type is robust to noise and maintains a certain protein expression pattern. In addition to this type of robustness, the course of differentiation, i.e., the timing at which cell differentiation progresses, is rather robust while the proportion regulation in the number of cell types is achieved, i.e., the number ratio of each cell type falls within a certain range after development [5,6,7]
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