Abstract
The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. To deal with such complex system, we additionally formulate a multiscale asymptotic method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state, with ER driving transitions between these states. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validates the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer.
Highlights
The ability of the ageing process to interfere with the robustness of the epigenetic regulation (ER) of differentiated phenotypes might suffice to promote tissue dysfunction and malignization [1].Fully committed somatic cells can spontaneously reprogram to pluripotent stem-like cells during the normal response to injury or damage in vivo [2]
Certain modifications of the structure and functioning of the protein/DNA complex called chromatin can allow adult, fully differentiated, cells to adopt a stem cell-like pluripotent state in a purely epigenetic manner, not involving changes in the underlying DNA sequence
It should be noted that in vivo reprogramming would be capable of maintaining tissue homeostasis provided the acquisition of pluripotency features is strictly transient and accompanied by an accurate replenishment of the specific cell types being lost
Summary
Committed somatic cells can spontaneously reprogram to pluripotent stem-like cells during the normal response to injury or damage in vivo [2] Such cellular processes involving dedifferentiation and cell-fate switching might constitute a fundamental element of a tissue’s capacity to self-repair and rejuvenate [3, 4]. In response to chronically permissive tissue environments for in vivo reprogramming, the occurrence of unrestrained epigenetic plasticity might permanently lock cells into self-renewing pluripotent cell states disabled for reparative differentiation and prone to tumorigenesis (see Fig 1) [1, 5,6,7,8] Central to such so-called stem-lock model for ageing and cancer [6, 9, 10] is the sufficient capacity of ER to drive cell fate in the absence of bona fide, initiating events. Robust and standardised approaches capable of capturing such fundamental stochastic aspects of ageing biology are mostly lacking
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