Effects of bidirectional phenotype switching on signal noise in a bacterial community.

Cells can sense and process various signals. Noise is inevitable in the cell signaling system. In a bacterial community, the mutual conversion between normal cells and persistent cells forms a bidirectional phenotype switching cascade, in which either one can be used as an upstream signal and the other as a downstream signal. In order to quantitatively describe the relationship between noise and signal amplification of each phenotype, the gain-fluctuation relationship is obtained by using the linear noise approximation of the master equation. Through the simulation of these theoretical formulas, it is found that the bidirectional phenotype switching can directly generate interconversion noise which is usually very small and almost negligible. In particular, the bidirectional phenotype switching can provide a global fluctuating environment, which will not only affect the values of noise and covariance, but also generate additional intrinsic noise. The additional intrinsic noise in each phenotype is the main part of the total noise and can be transmitted to the other phenotype. The transmitted noise is also a powerful supplement to the total noise. Therefore, the indirect impact of bidirectional phenotype switching is far greater than its direct impact, which may be one of the reasons why chronic infections caused by persistent cells are refractory to treat.

Noisy signal propagation and amplification in phenotypic transition cascade of colonic cells.

Like genes and proteins, cells can use biochemical networks to sense and process information. The differentiation of the cell state in colonic crypts forms a typical unidirectional phenotypic transitional cascade, in which stem cells differentiate into the transit-amplifying cells (TACs), and TACs continue to differentiate into fully differentiated cells. In order to quantitatively describe the relationship between the noise of each compartment and the amplification of signals, the gain factor is introduced, and the gain-fluctuation relation is obtained by using the linear noise approximation of the master equation. Through the simulation of these theoretical formulas, the characters of noise propagation and amplification are studied. It is found that the transmitted noise is an important part of the total noise in each downstream cell. Therefore, a small number of downstream cells can only cause its small inherent noise, but the total noise may be very large due to the transmitted noise. The influence of the transmitted noise may be the indirect cause of colon cancer. In addition, the total noise of the downstream cells always has a minimum value. As long as a reasonable value of the gain factor is selected, the number of cells in colonic crypts will be controlled within the normal range. This may be a good method to intervene the uncontrollable growth of tumor cells and effectively control the deterioration of colon cancer.

Fluctuation and noise propagation in phenotypic transition cascades of clonal populations.

Quantitative modeling of fluctuations of each phenotype is a crucial step towards a fundamental understanding of noise propagation through various phenotypic transition cascades. The theoretical formulas for noise propagation in various phenotypic transition cascades are derived by using the linear noise approximation of master equation and the logarithmic gain. By virtue of the theoretical formulas, we study the noise propagation in bidirectional and unidirectional phenotypic transition cascades, respectively. It is found that noise propagation in these two phenotypic transition cascades evidently differs: In the bidirectional cascade, a systemic random environment is provided by a correlated global component. The total noise of each phenotype is mainly determined by the intrinsic noise and the transmitted noise from other phenotypes. The intrinsic noise enlarged by interconversion through an added part shows a novel noise propagation mechanism. However, in the unidirectional cascade, the random environment of each downstream phenotype is provided by upstream phenotypes. The total noise of each downstream phenotype is mainly determined by the transmitted noises from upstream phenotypes. The intrinsic noise and the conversion noise can propagate in both bidirectional and unidirectional phenotypic transition cascades.

Fluctuations of cell population in a colonic crypt.

The number of stem cells in a colonic crypt is often very small, which leads to large intrinsic fluctuations in the cell population. Based on the model of cell population dynamics with linear feedback in a colonic crypt, we present a stochastic dynamics of the cell population [including stem cells (SCs), transit amplifying cells (TACs), and fully differentiated cells (FDCs)]. The Fano factor, covariance, and susceptibility formulas of the cell population around the steady state are derived by using the Langevin theory. In the range of physiologically reasonable parameter values, it is found that the stationary populations of TACs and FDCs exhibit an approximately threshold behavior as a function of the net growth rate of TACs, and the reproductions of TACs and FDCs can be classified into three regimens: controlled, crossover, and uncontrolled. With the increasing of the net growth rate of TACs, there is a maximum of the relative intrinsic fluctuations (i.e., the Fano factors) of TACs and FDCs in the crossover region. For a fixed differentiation rate and the net growth rate of SCs, the covariance of fluctuations between SCs and TACs has a maximum in the crossover region. However, the susceptibilities of both TACs and FDCs to the net growth rate of TACs have a minimum in the crossover region.