A Computational Model of

Chemotaxis-based Cell Aggregation

M. Eyiyurekli*, P.I. Lelkes** and D.E. Breen*
*Department of Computer Science **School of Biomedical Engineering, Science
College of Engineering and Health Systems

CTX-based cell aggregation Cell Model System Structure

• Chemotaxis (CTX) is the phenomenon where cells detect chemical Each cell is defined by a collection of parameters and actions. Yes
Separating? Separate
gradients and respond to the chemical stimulus by moving in the
direction of these gradients, either towards (positive CTX) or away • Number and the position of CTX receptors
No

(negative CTX) from the source. on the cell surface Random

Waking?
No
Attach Age
Motion
• Location of the cell
• Age Yes + Yes Yes

• Life cycle stage No Calculate FollowNo No

Die?
Yes
Dead
New Cell Quiescent? Collision?
• Multicellular aggregates and • Chemoattractant emission rate Gradient Gradient

eventually tissue-like assemblies • Diffusion radius (RMAX) No

are formed when individual cells • Proliferation rate No

attach to other cells. • Number of attached cells Proliferate?

No Save Yes
Emit
Daughter Yes state?
Cells

• Understanding the influence of the many • Emission and sensing of chemoattractors Save
components of CTX on overall cell • Gradient following & Brownian motion Start
aggregation should lead to a more • Proliferation
detailed understanding of cellular aggregation and organogenesis, and also • Collisions and adhesion • Cells live on a hexagonal grid • Chemical diffusion approximated by a 1/r concentration field
facilitate the development of novel technologies for tissue engineering based • Aging and cell death • Environment has toroidal topology • Assume chemical interaction stops beyond a certain distance
on controlling or directing these underlying biological processes. • Cells may attach to each other at six • Simulation time step is dynamically calculated for movements
distinct sites

Model Fine Tuning & Verification Parametric Studies

0.3 0.3 0.2 0.2

0.18 0.18
0.25 0.25
0.16 0.16

0.14 0.14
0.2 0.2

Proliferation Rate
0.12 0.12
0.15 0.15 0.1 0.1

0.08 0.08
0.1 0.1
0.06 0.06

0.05 0.05 0.04 0.04

0.02 0.02
0 0 0 0
1 3 5 7 9 11 13 15 17 19 1 3 5 7 9 11 13 15 17 19 Cell Velocity 1 3 5 7 9 11 13 15 17 19 1 3 5 7 9 11 13 15 17 19
Aggregate Size Aggregate Size Aggregate Size Aggregate Size
In vitro In silico In vitro In silico In vitro In silico In vitro In silico

Experimental Data Simulation Results 0.25 0.25 0.45 0.45

0.4 0.4

• Perform a 24-hour simulation 0.2 0.2

Quiescence 0.35 0.35

• Simulation initial conditions taken from experimental data 0.15 0.15

0.3 0.3

- Number of cells, aggregate distribution 0.25 0.25

0.2
0.2
• Compare simulation final results with experimental data 0.1 0.1
0.15 0.15

• The model is validated via a close fit to actual cell-cell aggregation data 0.05 0.05 0.1 0.1

obtained from 24-hour studies of PC12 cells. 0.05 0.05

• Initial model parameter values are taken from literature. 0 0 Separation Probability 0 0
1 3 5 7 9 11 13 15 17 19 1 3 5 7 9 11 13 15 17 19 1 3 5 7 9 11 13 15 17 19 1 3 5 7 9 11 13 15 17 19

• Parameter values are modified to produce optimal similarity between Aggregate Size Aggregate Size Aggregate Size Aggregate Size

In vitro In silico In vitro In silico

aggregate distributions.
In vitro In silico In vitro In silico

• Earth Mover’s Distance (EMD) is used to compare

two size distributions.
Results Future Work

• Extend to 3D
• Add hydrodynamic forces to simulate
bioreactor experiments
• Augment model to simulate cancer
development

• Simulations over a range of parameter

t=0 t = 6hr t = 12hr t = 18hr t = 24hr
values are performed with
- Proliferation & apoptosis rates
- Chemoattractant diffusion rate The initial results of our simulations demonstrate that our model is capable of producing cell aggregation distributions
- Cell velocity similar to those found in live cell experiments.
- Attachment/detachment probabilities