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Efficient Neural Differentiation using Single-Cell Culture of Human Embryonic Stem Cells
Published on: January 18, 2020
Single-cell data-driven mathematical model reveals possible molecular mechanisms of embryonic stem-cell
Xiao Tu1, Qin Ran Zhang1, Wei Zhang2
1School of Mathematics and Statistics, Wuhan University, Wuhan, P. R. China.
Abstract:
Embryonic development is widely studied due to its application in disease treatment. The published literature demonstrated that Krüppel-like factor 8(KLF8) plays an important role in modulating mesendoderm to definitive endoderm (DE) differentiation. However, it is not clear how KLF8 interacts with other key genes and affects the differentiation process. To qualitatively and quantitatively explore the molecular mechanisms of KLF8 during the differentiation of human embryonic stem cells (hESCs) in detail, we developed a mathematical model to describe the dynamics between KLF8 and two other significant genes, E-cadherin(CDH1) and Zinc-finger E-box-binding homeobox1(ZEB1). Based on the single-cell RNA-seq data, the model structure and parameters were obtained using particle swarm optimization (PSO). The bifurcation analysis and simulation results reveal that the system can exhibit a complex tristable transition, which corresponds to the three states of embryonic development at the single-cell level. We further predict that the novel important gene KLF8 promotes the formation of DE cells by reciprocal inhibition between CDH1 and KLF8 and promotion of the expression of ZEB1. These results may help to shed light on the biological mechanism in the differentiation process of hESCs.
Insights
Krüppel-like factor 8 (KLF8) is crucial for embryonic stem cell differentiation into definitive endoderm (DE). This study models KLF8 interactions, revealing its role in promoting DE formation through gene regulation.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Systems Biology
Background:
- Embryonic development research is vital for disease treatment applications.
- Krüppel-like factor 8 (KLF8) is known to modulate mesendoderm to definitive endoderm (DE) differentiation.
- The precise molecular mechanisms of KLF8 in hESC differentiation remain incompletely understood.
Purpose of the Study:
- To quantitatively and qualitatively explore the molecular mechanisms of KLF8 during human embryonic stem cell (hESC) differentiation.
- To develop a mathematical model describing the dynamics between KLF8, E-cadherin (CDH1), and Zinc-finger E-box-binding homeobox1 (ZEB1).
Main Methods:
- Development of a mathematical model for gene regulatory dynamics.
- Utilizing single-cell RNA-seq data for model parameterization.
- Employing particle swarm optimization (PSO) for model fitting.
- Performing bifurcation analysis and simulations.
Main Results:
- The developed model predicts a complex tristable transition in the system.
- This tristable transition corresponds to distinct embryonic developmental states at the single-cell level.
- KLF8 promotes DE cell formation via reciprocal inhibition with CDH1 and upregulation of ZEB1.
Conclusions:
- KLF8 plays a significant role in promoting definitive endoderm differentiation in hESCs.
- The study elucidates novel molecular interactions involving KLF8, CDH1, and ZEB1.
- Mathematical modeling provides insights into the complex biological mechanisms governing hESC differentiation.
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