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## WHAT IS IT?

This program is an example of modeling cellular proliferation during normal homeostasis of stem cells, as well as treatment with a small molecule agonist (CHIR) or antagnoist (IWP2) of the WNT signaling pathway. The WNT signaling pathway, a highly conserved evolutionary pathway, coordinates an array of complex biological processes during development and is responsible for the proper maintenance of tissue homeostasis. This model demonstrates the effects of adding a WNT signaling activator known as CHIR to a culture of stem cells. CHIR is a small molecule inhibitor of GSK3B which serves as an inhibitor of WNT signaling. The inhibiton of an inhibitor consequently results in activation of the WNT signaling pathway. Activation of WNT signaling results in increased cell proliferation. In addition, this model also includes another switch labeled IWP2. IWP2 is a small molecule that blocks the accumulation of B-catenin in the cytoplasm of a cell. B-catenin is necessary for the activation of WNT signaling, thus IWP2 serves as an inhibitor of WNT signaling. Cell proliferation is consequently stopped following inhibiton of WNT signaling via IWP2.

## HOW IT WORKS

In this model, each cell checks the state of itself and its eight surrounding neighbors and then sets itself to either proliferate or maintain quiescence. During homeostasis, when neither the CHIR nor IWP2 switches are ON, cells will proliferate if there are exactly 3 neighbors. Otherwise, cells will remain in a quiescent state. In the event the CHIR switch is turned ON, cells will again check their surrounding eight neighbors. If there are greater than 3 neighbors the cells will proliferate. In the event the IWP2 switch is turned ON (and CHIR switch OFF), cells will check their surrounding neighbors and if there are exactly 3 cells, cells will not proliferate.

## HOW TO USE IT

The INITIAL_SEEDING_DENSITY slider determines the initial density of the cells that are alive. SEED CELLS places these cells in the environment. GO ONCE runs the rule once. GO FOREVER runs the rule forever until the button is pressed again to stop.

If you want to draw your own pattern, use the DRAW-CELLS button and then use the mouse to "draw" in the environment.

The user can toggle between using the CHIR and IWP2 switches to observe the effects the presence of these small molecules has on cell proliferation.

## THINGS TO NOTICE

What are the key differences between "normal" cell proliferation and treatment with either CHIR or IWP2?

What happens when both the CHIR and IWP2 switches are turned ON at the same time?

## THINGS TO TRY

Try playing around with the initial seeding density and how cell proliferation is affected by the addition of each switch.

## RELATED MODELS

Cellular Automata - Life - the model presented here draws from the principles of the Life model to demonstrate cellular proliferation.

## CREDITS AND REFERENCES

Chen et al., Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Natural Chemical Biology 2009.

Huang et al. Activation of Wnt/B-catenin signaling via GSK3 inhibitors direct differentiation of human adipose stem cells into functional hepatocytes. Scientific Reports 2017.

Teo JL, Kahn M. The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators. Advanced Drug Delivery Reviews 2010.