Abstract
Cellular reprogramming has been recently intensively studied experimentally. We developed a global potential landscape and kinetic path framework to explore a human stem cell developmental network composed of 52 genes. We uncovered the underlying landscape for the stem cell network with two basins of attractions representing stem and differentiated cell states, quantified and exhibited the high dimensional biological paths for the differentiation and reprogramming process, connecting the stem cell state and differentiated cell state. Both the landscape and non-equilibrium curl flux determine the dynamics of cell differentiation jointly. Flux leads the kinetic paths to be deviated from the steepest descent gradient path, and the corresponding differentiation and reprogramming paths are irreversible. Quantification of paths allows us to find out how the differentiation and reprogramming occur and which important states they go through. We show the developmental process proceeds as moving from the stem cell basin of attraction to the differentiation basin of attraction. The landscape topography characterized by the barrier heights and transition rates quantitatively determine the global stability and kinetic speed of cell fate decision process for development. Through the global sensitivity analysis, we provided some specific predictions for the effects of key genes and regulation connections on the cellular differentiation or reprogramming process. Key links from sensitivity analysis and biological paths can be used to guide the differentiation designs or reprogramming tactics.
Highlights
Human pluripotent stem cells have the potential to produce any tissues in the body, which provides the motivation for many researchers to investigate the cellular reprogramming
We investigated the kinetics or speed of differentiation and reprogramming according to the mean first passage time (MFPT), in order to further quantify the dynamics of differentiation and reprogramming process
Landscape shows that the stem cell gene regulatory network has two stable basins of attractions at specific parameter regions, one of which represents the pluripotent stem cell state and the other of which represents the differentiation state
Summary
Human pluripotent stem cells have the potential to produce any tissues in the body, which provides the motivation for many researchers to investigate the cellular reprogramming. Understanding mechanisms of cellular differentiation and reprogramming as well as finding the optimal reprogramming pathway become very important for the application of iPSC This requires a systematic and global approach to explore underlying gene regulatory networks with marker genes and mutual regulations between them. The epigenetic landscape concept has been proposed to explain the development and differentiation of the cells as a metaphor [7], and provided a quantitative way of understanding the dynamics of gene regulatory system that drive cell development This picture has been quantitatively realized through exploration of the global nature of the network in terms of probabilistic landscape framework [8,9,10,11,12,13,14,15,16,17].
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