1. Modeling Chemotaxis, Cell Adhesion and Cell Sorting. Examples with Dictyostelium Eirikur Pálsson Dept of Biology, Simon Fraser University

3. Throughout gastrulation and embryogenesis. In wound healing. Carcinoma cell invasion. Limb bud regeneration. Cell movement in Dictyostelium discoideum. Examples of Processes Where Cell Movement Is Important:

4. Purpose of a Cell Movement model Visualization of cell movements in 3-D Understand how simple cell-cell interactions, signaling and adhesion lead to complex cell movements Simplification; Revealing the most important things Gives constraints. Suggests what behavior is possible

5. Introduction Design of Model Results Conclusions & Future Work Outline

7. The basic unit of the model is an ellipsoidal cell Deformation of the cell depends on the history of the forces acting on it The cell conserves volume with variable ellipsoidal semi-axes The cell may adhere to other cells or to the substrate When the cell moves it sends out a pseudopod, attaches it to either a neighbor or the surface The cell responds to chemotactic signals The Model.

8. A Representation of the Deformability of Each Axis

9. didi djdj

10. Rotation

11. Forces (static)

12. Force equations Equation of motion

13. All the neighbor cells are found The chemical gradient around each cell is calculated The cells orient towards the chemical gradient and apply an active force in that direction All the forces acting on a cell are determined. These are of two types; The passive and the active forces The cells are moved and deformed according to the equations of motion The chemical concentration is updated. Temporal Evolution of the Model

14. R Foty 1996

17. Sorting E aa,E bb > E ab E ab > E aa, E bb E bb > E ab >E aa Separation Random

18. Limb Bud Pigm. Epith. Heart Liver N. Retina Green Red Yellow Blue Orange Adhesion ColorType 20.1 12.6 8.5 4.6 1.6 R Foty 1996

20. Sorting Time Sorting Time Sorting: With or Without Random Cell Movement Sorting: Changing Cell Stiffness and Adhesion Normal Cell Stiffer Cell Stiffer and more Adhesive Cell Not Random Random Motion

21. Sorting of Pre-spore and Pre-Stalk Cells Takeuchi 1986

22. Sorting due to specific Cell Adhesion

23. Dictyostelium discoideum Life Cycle

24. Camp Waves During Aggregation 1 mm K Lee Princeton U

25. Aggregation (Firtel)

27. Simulations of Dictyostelium discoideum Aggregation in Response to cAMP signals.

28. Aggregation. Pacemaker Cells in Red

29. Aggregation. 1 to 1 Pacemaker Cells in Red

30. Aggregation,1-1. Reduced Diffusion

31. Bonner 1999

32. Simulations of 2-D slugs The Red Cells in the front are cAMP Pacemakers

33. Slug with cAMP wave

34. Slug moving straight, Pacemaker graft

35. Cell Sorting. The Chemotactic force is 50 % Larger in the Grey Cells

36. Slug with 2 different Cell types, same adhesion

37. Slug with 2 different cell types, specific cell adhesion Grey cells more adhesive than green

38. Thicker Slug with 2 different cell types, specific cell adhesion Grey cells more adhesive than green

39. Thicker Slug with 2 different cell types, specific cell adhesion Grey cells more adhesive than green (Cross section)

40. Conclusions The model reproduces well the observed behavior and properties of cell aggregates The chemotactic movement of cells in response to a cAMP wave are in qualitative agreement with experiments New Findings Random movement, cell stiffness and cell adhesion affect the rate of cell sorting Cell specific adhesion enhances chemotactic sorting and may be necessary to achieve cell sorting in a timely manner