Human embryonic stem cells (hESC) have unique cell cycle behavior and are typically characterized by a shortened G1 phase which increases upon differentiation. However, limited work has been done in the area of mechanistic information and dynamics of cell cycle transition from undifferentiated to mature cells. Our objective is to represent these unique dynamics of cell cycle transition in (hESC) using an integrated experimental and computational approach. To capture cell cycle behavior at multiple scales, two parallel models were developed. Our single cell model, employing a system of ordinary differential equations (ODE), is able to capture the unique hESC G1-S transition, including shortened G1 time, which gradually lengthens, but does not arrest, upon differentiation. hESC molecular dynamics are appropriately captured, including low levels of CKI and cyclin D. Inclusion of miRNA is necessary to capture the system's unique behavior.  To describe population behavior, a cellular automaton model was developed, with the state of the cell being defined by the cell cycle phase which the cell is in. This model is able to accurately predict phase resident time distributions from experimentally synchronized hESC. The estimated parameters led to excellent agreement with experimental dynamics, with predictions validated by synchronization/BrdU and CFSE experiments. These multi-scale dynamics of the ESC cell cycle cannot be fully comprehended without computational support, and it has been shown herein that mathematical modeling of the system extracts more information than would be possible with an experimental approach alone.

Capturing the unique cell-cycle dynamics of human embryonic stem cell during self-renewal and differentiation

247th National Meeting (2014)

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