Controlling stochasticity in epithelial-mesenchymal transition through multiple intermediate cellular states

Abstract

Epithelial-mesenchymal transition (EMT) is an instance of cellular plasticity that plays critical roles in development, regeneration and cancer progression. Recent studies indicate that the transition between epithelial and mesenchymal states is a multi-step and reversible process in which several intermediate phenotypes might coexist. These intermediate states correspond to various forms of stem-like cells in the EMT system, but the function of the multi-step transition or the multiple stem cell phenotypes is unclear. Here, we use mathematical models to show that multiple intermediate phenotypes in the EMT system help to attenuate the overall fluctuations of the cell population in terms of phenotypic compositions, thereby stabilizing a heterogeneous cell population in the EMT spectrum. We found that the ability of the system to attenuate noise on the intermediate states depends on the number of intermediate states, indicating the stem-cell population is more stable when it has more sub-states. Our study reveals a novel advantage of multiple intermediate EMT phenotypes in terms of systems design, and it sheds light on the general design principle of heterogeneous stem cell population.

Mean-Independent Noise Control of Cell Fates via Intermediate States

“…This suggests that MINC may be a general phenomenon related to the existence of intermediate states and probably exists in other GRNs. Computational simulations of epithelial-mesenchymal transitions (EMTs) recently has shown that increased numbers of intermediate states attenuate noise in cellular fate decisions ( Ta et al., 2016 ), which is analogous to our predictions of how pooling in the intermediate state reduces noise. Primed lineages in hematopoietic stem cells can be represented as an intermediate state with reversible changes, which could explain data showing mean-independent noise attenuation due to a lineage commitment factor ( van Galen et al., 2014 ).…”

A plausible accelerating function of intermediate states in cancer metastasis

“…That is, the more intermediate EMT states in one cancer type, the better the chance it will metastasize. A complementary feature of multiple intermediate phenotypes was reported to stabilize the cancer stem cell population [51]. Thus, the malignancy level can be quantified by the number of potential intermediate EMT states.…”

Exploring intermediate cell states through the lens of single cells

“…Models have predicted that multiple ICSs can facilitate the attenuation of fluctuating cell populations [ 74 ]. By absorbing some of the noise, these additional states serve as ‘buffers’ against environmental fluctuations, thereby preventing imbalances of cells in terminal states.…”