Abstract
Stem cells, with their capacity to self-renew and to differentiate to more specialized cell types, play a key role to maintain homeostasis in adult tissues. To investigate how, in the dynamic stochastic environment of a tissue, non-genetic diversity and the precise balance between proliferation and differentiation are achieved, it is necessary to understand the molecular mechanisms of the stem cells in decision making process. By focusing on the impact of stochasticity, we proposed a computational model describing the regulatory circuitry as a tri-stable dynamical system to reveal the mechanism which orchestrate this balance. Our model explains how the distribution of noise in genes, linked to the cell regulatory networks, affects cell decision-making to maintain homeostatic state. The noise effect on tissue homeostasis is achieved by regulating the probability of differentiation and self-renewal through symmetric and/or asymmetric cell divisions. Our model reveals, when mutations due to the replication of DNA in stem cell division, are inevitable, how mutations contribute to either aging gradually or the development of cancer in a short period of time. Furthermore, our model sheds some light on the impact of more complex regulatory networks on the system robustness against perturbations.
Highlights
Throughout development, stem cells play a key role during multiple morphogenetic processes, such as tissue growth, regeneration, and repair
Inspired by previous studies that revealed the impact of regulatory networks on the stability of biological systems [14, 27, 33, 41, 55,56,57,58, 11], here, we introduce a tristable switch described by a set of ordinary differential equations (ODEs) which is a formal framework to study the regulatory circuitries [36, 59, 60,61,62,63]
To study the regulatory mechanism which provides the proliferation/differentiation balance in homeostatic state, we proposed a computational model described by a set of ordinary differential equations (ODEs) which was previously used in several studies to model the regulatory circuitries as tri-stable dynamical systems [36, 59]
Summary
Throughout development, stem cells play a key role during multiple morphogenetic processes, such as tissue growth, regeneration, and repair. Stem cells are characterized by their capacity to self-renew and to differentiate to more specialized cell types [1, 2] and a balance between these two processes is necessary to maintain homeostasis in adult tissues [3,4,5,6]. To develop a tissue with hundreds of different cell types from a single stem cell, a non-genetic diversifying mechanism is required. Understanding the underlying mechanisms which regulate the non-genetic diversity and orchestrate the stem cell proliferation/differentiation balance in the dynamic stochastic environment of a tissue is a central challenge in adult stem cell biology [7].
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