Quantifying cell fate decisions for differentiation and reprogramming of a human stem cell network: landscape and biological paths

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 o...

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Bibliographic Details
Published in:PLoS computational biology 2013-08, Vol.9 (8), p.e1003165-e1003165
Main Authors: Li, Chunhe, Wang, Jin
Format: Article
Language:English
Subjects:
Basins
Biology
Cell differentiation
Cell Differentiation - physiology
Computational Biology
Decision making
Experiments
Gene expression
Gene Regulatory Networks
Genetic engineering
Genetic Markers
Humans
Kinetics
Models, Biological
Physics
Physiological aspects
Regulation
Sensitivity analysis
Stem cells
Stem Cells - cytology
Studies
Transplants & implants
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Summary: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.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1003165