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This tutorial was generated from the file projects/CellBasedComparison2017/test/TestCellSortingLiteratePaper.hpp at revision r27522. Note that the code is given in full at the bottom of the page.

Adhesion Example

On this wiki page we describe in detail the code that is used to run this example from the paper.

The easiest way to visualize these simulations is with Paraview.

EmbedYoutube(4YZp_WmBZTI)

Code overview

The first thing to do is to include the necessary header files.

#include <cxxtest/TestSuite.h>

// Must be included before other cell_based headers
#include "CellBasedSimulationArchiver.hpp"

#include "AbstractCellBasedWithTimingsTestSuite.hpp"
#include "CellLabel.hpp"
#include "SmartPointers.hpp"
#include "CellsGenerator.hpp"
#include "UniformG1GenerationalCellCycleModel.hpp"
#include "TransitCellProliferativeType.hpp"
#include "DifferentiatedCellProliferativeType.hpp"

#include "HeterotypicBoundaryLengthWriter.hpp"

#include "OffLatticeSimulation.hpp"
#include "VertexBasedCellPopulation.hpp"
#include "HoneycombVertexMeshGenerator.hpp"
#include "NagaiHondaDifferentialAdhesionForce.hpp"
#include "RandomMotionForce.hpp"
#include "SimpleTargetAreaModifier.hpp"

#include "MeshBasedCellPopulationWithGhostNodes.hpp"
#include "HoneycombMeshGenerator.hpp"
#include "DifferentialAdhesionGeneralisedLinearSpringForce.hpp"
#include "RandomMotionForce.hpp"

#include "OnLatticeSimulation.hpp"
#include "CellPopulationAdjacencyMatrixWriter.hpp"

#include "CaBasedCellPopulation.hpp"
#include "ShovingCaBasedDivisionRule.hpp"
#include "RandomCaSwitchingUpdateRule.hpp"
#include "DifferentialAdhesionCaSwitchingUpdateRule.hpp"

#include "PottsBasedCellPopulation.hpp"
#include "PottsMeshGenerator.hpp"
#include "VolumeConstraintPottsUpdateRule.hpp"
#include "SurfaceAreaConstraintPottsUpdateRule.hpp"
#include "AdhesionPottsUpdateRule.hpp"
#include "DifferentialAdhesionPottsUpdateRule.hpp"

#include "CellIdWriter.hpp"
#include "CellMutationStatesWriter.hpp"

#include "PetscSetupAndFinalize.hpp"

This is where you can set parameters to be used in all the simulations.

static const double M_TIME_TO_STEADY_STATE = 10; //10
static const double M_TIME_FOR_SIMULATION = 100; //100
static const double M_NUM_CELLS_ACROSS = 20; //20 // this ^2 cells
static const double M_CELL_FLUCTUATION = 1.0;

class TestCellSortingLiteratePaper : public AbstractCellBasedWithTimingsTestSuite
{
private:

This is a helper method to randomly label cells add is used in all simulations.

    void RandomlyLabelCells(std::list<CellPtr>& rCells, boost::shared_ptr<AbstractCellProperty> pLabel, double labelledRatio)
    {
        for (std::list<CellPtr>::iterator cell_iter = rCells.begin();
             cell_iter != rCells.end();
             ++cell_iter)
        {
            if (RandomNumberGenerator::Instance()->ranf() < labelledRatio)
            {
               (*cell_iter)->AddCellProperty(pLabel);
            }
        }
    }

public:

CA

Simulate a population of cells exhibiting cell sorting using the Cellular Automaton model.

    void TestCaBasedMonolayerCellSorting()
    {
        // Create a simple 2D PottsMesh
        unsigned domain_wide = 2*M_NUM_CELLS_ACROSS;

        PottsMeshGenerator<2> generator(domain_wide, 0, 0, domain_wide, 0, 0);
        PottsMesh<2>* p_mesh = generator.GetMesh();

        p_mesh->Translate(-(double)domain_wide*0.5 + 0.5,-(double)domain_wide*0.5 + 0.5);

        // Specify where cells lie
        std::vector<unsigned> location_indices;
        for (unsigned i=0; i<M_NUM_CELLS_ACROSS; i++)
        {
          for (unsigned j=0; j<M_NUM_CELLS_ACROSS; j++)
          {
              unsigned offset = (domain_wide+1) * (domain_wide-M_NUM_CELLS_ACROSS)/2;
              location_indices.push_back(offset + j + i * domain_wide );
          }
        }
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, location_indices.size(), p_differentiated_type);

        // Create cell population
        CaBasedCellPopulation<2> cell_population(*p_mesh, cells, location_indices);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        OnLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Ca");
        simulator.SetDt(0.01);
        simulator.SetSamplingTimestepMultiple(100);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Add Division Rule
        boost::shared_ptr<AbstractCaBasedDivisionRule<2> > p_division_rule(new ShovingCaBasedDivisionRule<2>());
        cell_population.SetCaBasedDivisionRule(p_division_rule);

        // Add switching Update Rule
        MAKE_PTR(DifferentialAdhesionCaSwitchingUpdateRule<2u>, p_switching_update_rule);
        p_switching_update_rule->SetLabelledCellLabelledCellAdhesionEnergyParameter(0.1);
        p_switching_update_rule->SetLabelledCellCellAdhesionEnergyParameter(0.2);
        p_switching_update_rule->SetCellCellAdhesionEnergyParameter(0.1);
        p_switching_update_rule->SetCellBoundaryAdhesionEnergyParameter(0.2);
        p_switching_update_rule->SetLabelledCellBoundaryAdhesionEnergyParameter(0.4);
        p_switching_update_rule->SetTemperature(0.1);
        simulator.AddUpdateRule(p_switching_update_rule);

        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // modify parameters
        p_switching_update_rule->SetTemperature(0.1*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

CP

Simulate a population of cells exhibiting cell sorting using the Cellular Potts model.

    void TestPottsMonolayerCellSorting()
    {
        // Create a simple 2D PottsMesh
        unsigned element_size = 4;
        unsigned domain_size = M_NUM_CELLS_ACROSS * element_size * 3; // Three times the initial domain size
        PottsMeshGenerator<2> generator(domain_size, M_NUM_CELLS_ACROSS, element_size, domain_size, M_NUM_CELLS_ACROSS, element_size);
        PottsMesh<2>* p_mesh = generator.GetMesh();

        // Create cells
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, p_mesh->GetNumElements(), p_differentiated_type);

        // Create cell population
        PottsBasedCellPopulation<2> cell_population(*p_mesh, cells);
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set the Temperature
        cell_population.SetTemperature(0.2); //Default is 0.1

        // Set up cell-based simulation and output directory
        OnLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Potts");

        // Set time step and end time for simulation
        simulator.SetDt(0.01);
        simulator.SetSamplingTimestepMultiple(100);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create update rules and pass to the simulation
        MAKE_PTR(VolumeConstraintPottsUpdateRule<2>, p_volume_constraint_update_rule);
        p_volume_constraint_update_rule->SetMatureCellTargetVolume(16); // i.e 4x4 cells
        p_volume_constraint_update_rule->SetDeformationEnergyParameter(0.1);
        simulator.AddUpdateRule(p_volume_constraint_update_rule);

        MAKE_PTR(SurfaceAreaConstraintPottsUpdateRule<2>, p_surface_constraint_update_rule);
        p_surface_constraint_update_rule->SetMatureCellTargetSurfaceArea(16); // i.e 4x4 cells
        p_surface_constraint_update_rule->SetDeformationEnergyParameter(0.01);//0.01
        simulator.AddUpdateRule(p_surface_constraint_update_rule);

        MAKE_PTR(DifferentialAdhesionPottsUpdateRule<2>, p_differential_adhesion_update_rule);
        p_differential_adhesion_update_rule->SetLabelledCellLabelledCellAdhesionEnergyParameter(0.1);
        p_differential_adhesion_update_rule->SetLabelledCellCellAdhesionEnergyParameter(0.5); // 1.0
        p_differential_adhesion_update_rule->SetCellCellAdhesionEnergyParameter(0.1); //0.1
        p_differential_adhesion_update_rule->SetCellBoundaryAdhesionEnergyParameter(0.2); // 1.0
        p_differential_adhesion_update_rule->SetLabelledCellBoundaryAdhesionEnergyParameter(1.0); // 2.0
        simulator.AddUpdateRule(p_differential_adhesion_update_rule);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust Parameters
        dynamic_cast <PottsBasedCellPopulation<2>*>(&(simulator.rGetCellPopulation()))->SetTemperature(0.2*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

OS

Simulate a population of cells exhibiting cell sorting using the Overlapping Sphere model.

    void TestNodeBasedMonolayerCellSorting()
    {
        // Create a simple mesh
        HoneycombMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS, 0);
        TetrahedralMesh<2,2>* p_generating_mesh = generator.GetMesh();

		//Extended to allow sorting for longer distances
        double cut_off_length = 2.5;

        // Convert this to a NodesOnlyMesh
        NodesOnlyMesh<2> mesh;
        mesh.ConstructNodesWithoutMesh(*p_generating_mesh, cut_off_length);

        // Set up cells, one for each Node
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, mesh.GetNumNodes(), p_differentiated_type);

        // Create cell population
        NodeBasedCellPopulation<2> cell_population(mesh, cells);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Node");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create a force law and pass it to the simulation
        MAKE_PTR(DifferentialAdhesionGeneralisedLinearSpringForce<2>, p_differential_adhesion_force);
        p_differential_adhesion_force->SetMeinekeSpringStiffness(50.0);
        p_differential_adhesion_force->SetHomotypicLabelledSpringConstantMultiplier(1.0);
        p_differential_adhesion_force->SetHeterotypicSpringConstantMultiplier(0.1);
        p_differential_adhesion_force->SetCutOffLength(cut_off_length);
        simulator.AddForce(p_differential_adhesion_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.05); //0.1 causes dissasociation, 0.001 is not enough
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.05*M_CELL_FLUCTUATION); //0.1 causes dissasociation

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

VT

Simulate a population of cells exhibiting cell sorting using the Voronoi tesselation model.

    void TestMeshBasedWithGhostsMonolayerCellSorting()
    {
        // Create a simple mesh
        unsigned num_ghosts = 20;
        HoneycombMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS, num_ghosts);
        MutableMesh<2,2>* p_mesh = generator.GetMesh();

        // Set up cells, one for each non ghost Node
        std::vector<unsigned> location_indices = generator.GetCellLocationIndices();
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, location_indices.size(), p_differentiated_type);

        // Create cell population
        MeshBasedCellPopulationWithGhostNodes<2> cell_population(*p_mesh, cells, location_indices);
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Mesh");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create a force law and pass it to the simulation
        MAKE_PTR(DifferentialAdhesionGeneralisedLinearSpringForce<2>, p_differential_adhesion_force);
        p_differential_adhesion_force->SetMeinekeSpringStiffness(50.0);
        p_differential_adhesion_force->SetHomotypicLabelledSpringConstantMultiplier(1.0);
        p_differential_adhesion_force->SetHeterotypicSpringConstantMultiplier(0.1);
        simulator.AddForce(p_differential_adhesion_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.1);
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.1*M_CELL_FLUCTUATION); //0.1 causes dissasociation

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

VM

Simulate a population of cells exhibiting cell sorting using the Cell Vertex model.

    void TestVertexMonolayerCellSorting()
    {
        // Create a simple 2D MutableVertexMesh
        HoneycombVertexMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS);
        MutableVertexMesh<2,2>* p_mesh = generator.GetMesh();
        p_mesh->SetCellRearrangementThreshold(0.1);

        // Slows things down but can use a larger timestep and diffusion forces
        //p_mesh->SetCheckForInternalIntersections(true);

        // Set up cells, one for each VertexElement
        std::vector<CellPtr> cells;
        boost::shared_ptr<AbstractCellProperty> p_cell_type(CellPropertyRegistry::Instance()->Get<DifferentiatedCellProliferativeType>());
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, p_mesh->GetNumElements(), p_cell_type);

        for (unsigned i=0; i<cells.size(); i++)
        {
            // Set a target area rather than setting a growth modifier. (the modifiers don't work correctly as making very long G1 phases)
            cells[i]->GetCellData()->SetItem("target area", 1.0);
        }

        // Create cell population
        VertexBasedCellPopulation<2> cell_population(*p_mesh, cells);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Vertex");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Set up force law and pass it to the simulation
        MAKE_PTR(NagaiHondaDifferentialAdhesionForce<2>, p_force);
        p_force->SetNagaiHondaDeformationEnergyParameter(50.0);
        p_force->SetNagaiHondaMembraneSurfaceEnergyParameter(1.0);
        p_force->SetNagaiHondaCellCellAdhesionEnergyParameter(1.0);
        p_force->SetNagaiHondaLabelledCellCellAdhesionEnergyParameter(2.0);
        p_force->SetNagaiHondaLabelledCellLabelledCellAdhesionEnergyParameter(1.0);
        p_force->SetNagaiHondaCellBoundaryAdhesionEnergyParameter(10.0);
        p_force->SetNagaiHondaLabelledCellBoundaryAdhesionEnergyParameter(20.0);
        simulator.AddForce(p_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.1);
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.1*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }
};

Code

The full code is given below

File name `TestCellSortingLiteratePaper.hpp`

#include <cxxtest/TestSuite.h>

// Must be included before other cell_based headers
#include "CellBasedSimulationArchiver.hpp"

#include "AbstractCellBasedWithTimingsTestSuite.hpp"
#include "CellLabel.hpp"
#include "SmartPointers.hpp"
#include "CellsGenerator.hpp"
#include "UniformG1GenerationalCellCycleModel.hpp"
#include "TransitCellProliferativeType.hpp"
#include "DifferentiatedCellProliferativeType.hpp"

#include "HeterotypicBoundaryLengthWriter.hpp"

#include "OffLatticeSimulation.hpp"
#include "VertexBasedCellPopulation.hpp"
#include "HoneycombVertexMeshGenerator.hpp"
#include "NagaiHondaDifferentialAdhesionForce.hpp"
#include "RandomMotionForce.hpp"
#include "SimpleTargetAreaModifier.hpp"

#include "MeshBasedCellPopulationWithGhostNodes.hpp"
#include "HoneycombMeshGenerator.hpp"
#include "DifferentialAdhesionGeneralisedLinearSpringForce.hpp"
#include "RandomMotionForce.hpp"

#include "OnLatticeSimulation.hpp"
#include "CellPopulationAdjacencyMatrixWriter.hpp"

#include "CaBasedCellPopulation.hpp"
#include "ShovingCaBasedDivisionRule.hpp"
#include "RandomCaSwitchingUpdateRule.hpp"
#include "DifferentialAdhesionCaSwitchingUpdateRule.hpp"

#include "PottsBasedCellPopulation.hpp"
#include "PottsMeshGenerator.hpp"
#include "VolumeConstraintPottsUpdateRule.hpp"
#include "SurfaceAreaConstraintPottsUpdateRule.hpp"
#include "AdhesionPottsUpdateRule.hpp"
#include "DifferentialAdhesionPottsUpdateRule.hpp"

#include "CellIdWriter.hpp"
#include "CellMutationStatesWriter.hpp"

#include "PetscSetupAndFinalize.hpp"

static const double M_TIME_TO_STEADY_STATE = 10; //10
static const double M_TIME_FOR_SIMULATION = 100; //100
static const double M_NUM_CELLS_ACROSS = 20; //20 // this ^2 cells
static const double M_CELL_FLUCTUATION = 1.0;

class TestCellSortingLiteratePaper : public AbstractCellBasedWithTimingsTestSuite
{
private:

    void RandomlyLabelCells(std::list<CellPtr>& rCells, boost::shared_ptr<AbstractCellProperty> pLabel, double labelledRatio)
    {
        for (std::list<CellPtr>::iterator cell_iter = rCells.begin();
             cell_iter != rCells.end();
             ++cell_iter)
        {
            if (RandomNumberGenerator::Instance()->ranf() < labelledRatio)
            {
               (*cell_iter)->AddCellProperty(pLabel);
            }
        }
    }

public:

    void TestCaBasedMonolayerCellSorting()
    {
        // Create a simple 2D PottsMesh
        unsigned domain_wide = 2*M_NUM_CELLS_ACROSS;

        PottsMeshGenerator<2> generator(domain_wide, 0, 0, domain_wide, 0, 0);
        PottsMesh<2>* p_mesh = generator.GetMesh();

        p_mesh->Translate(-(double)domain_wide*0.5 + 0.5,-(double)domain_wide*0.5 + 0.5);

        // Specify where cells lie
        std::vector<unsigned> location_indices;
        for (unsigned i=0; i<M_NUM_CELLS_ACROSS; i++)
        {
          for (unsigned j=0; j<M_NUM_CELLS_ACROSS; j++)
          {
              unsigned offset = (domain_wide+1) * (domain_wide-M_NUM_CELLS_ACROSS)/2;
              location_indices.push_back(offset + j + i * domain_wide );
          }
        }
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, location_indices.size(), p_differentiated_type);

        // Create cell population
        CaBasedCellPopulation<2> cell_population(*p_mesh, cells, location_indices);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        OnLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Ca");
        simulator.SetDt(0.01);
        simulator.SetSamplingTimestepMultiple(100);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Add Division Rule
        boost::shared_ptr<AbstractCaBasedDivisionRule<2> > p_division_rule(new ShovingCaBasedDivisionRule<2>());
        cell_population.SetCaBasedDivisionRule(p_division_rule);

        // Add switching Update Rule
        MAKE_PTR(DifferentialAdhesionCaSwitchingUpdateRule<2u>, p_switching_update_rule);
        p_switching_update_rule->SetLabelledCellLabelledCellAdhesionEnergyParameter(0.1);
        p_switching_update_rule->SetLabelledCellCellAdhesionEnergyParameter(0.2);
        p_switching_update_rule->SetCellCellAdhesionEnergyParameter(0.1);
        p_switching_update_rule->SetCellBoundaryAdhesionEnergyParameter(0.2);
        p_switching_update_rule->SetLabelledCellBoundaryAdhesionEnergyParameter(0.4);
        p_switching_update_rule->SetTemperature(0.1);
        simulator.AddUpdateRule(p_switching_update_rule);

        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // modify parameters
        p_switching_update_rule->SetTemperature(0.1*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

    void TestPottsMonolayerCellSorting()
    {
        // Create a simple 2D PottsMesh
        unsigned element_size = 4;
        unsigned domain_size = M_NUM_CELLS_ACROSS * element_size * 3; // Three times the initial domain size
        PottsMeshGenerator<2> generator(domain_size, M_NUM_CELLS_ACROSS, element_size, domain_size, M_NUM_CELLS_ACROSS, element_size);
        PottsMesh<2>* p_mesh = generator.GetMesh();

        // Create cells
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, p_mesh->GetNumElements(), p_differentiated_type);

        // Create cell population
        PottsBasedCellPopulation<2> cell_population(*p_mesh, cells);
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set the Temperature
        cell_population.SetTemperature(0.2); //Default is 0.1

        // Set up cell-based simulation and output directory
        OnLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Potts");

        // Set time step and end time for simulation
        simulator.SetDt(0.01);
        simulator.SetSamplingTimestepMultiple(100);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create update rules and pass to the simulation
        MAKE_PTR(VolumeConstraintPottsUpdateRule<2>, p_volume_constraint_update_rule);
        p_volume_constraint_update_rule->SetMatureCellTargetVolume(16); // i.e 4x4 cells
        p_volume_constraint_update_rule->SetDeformationEnergyParameter(0.1);
        simulator.AddUpdateRule(p_volume_constraint_update_rule);

        MAKE_PTR(SurfaceAreaConstraintPottsUpdateRule<2>, p_surface_constraint_update_rule);
        p_surface_constraint_update_rule->SetMatureCellTargetSurfaceArea(16); // i.e 4x4 cells
        p_surface_constraint_update_rule->SetDeformationEnergyParameter(0.01);//0.01
        simulator.AddUpdateRule(p_surface_constraint_update_rule);

        MAKE_PTR(DifferentialAdhesionPottsUpdateRule<2>, p_differential_adhesion_update_rule);
        p_differential_adhesion_update_rule->SetLabelledCellLabelledCellAdhesionEnergyParameter(0.1);
        p_differential_adhesion_update_rule->SetLabelledCellCellAdhesionEnergyParameter(0.5); // 1.0
        p_differential_adhesion_update_rule->SetCellCellAdhesionEnergyParameter(0.1); //0.1
        p_differential_adhesion_update_rule->SetCellBoundaryAdhesionEnergyParameter(0.2); // 1.0
        p_differential_adhesion_update_rule->SetLabelledCellBoundaryAdhesionEnergyParameter(1.0); // 2.0
        simulator.AddUpdateRule(p_differential_adhesion_update_rule);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust Parameters
        dynamic_cast <PottsBasedCellPopulation<2>*>(&(simulator.rGetCellPopulation()))->SetTemperature(0.2*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

    void TestNodeBasedMonolayerCellSorting()
    {
        // Create a simple mesh
        HoneycombMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS, 0);
        TetrahedralMesh<2,2>* p_generating_mesh = generator.GetMesh();

		//Extended to allow sorting for longer distances
        double cut_off_length = 2.5;

        // Convert this to a NodesOnlyMesh
        NodesOnlyMesh<2> mesh;
        mesh.ConstructNodesWithoutMesh(*p_generating_mesh, cut_off_length);

        // Set up cells, one for each Node
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, mesh.GetNumNodes(), p_differentiated_type);

        // Create cell population
        NodeBasedCellPopulation<2> cell_population(mesh, cells);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Node");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create a force law and pass it to the simulation
        MAKE_PTR(DifferentialAdhesionGeneralisedLinearSpringForce<2>, p_differential_adhesion_force);
        p_differential_adhesion_force->SetMeinekeSpringStiffness(50.0);
        p_differential_adhesion_force->SetHomotypicLabelledSpringConstantMultiplier(1.0);
        p_differential_adhesion_force->SetHeterotypicSpringConstantMultiplier(0.1);
        p_differential_adhesion_force->SetCutOffLength(cut_off_length);
        simulator.AddForce(p_differential_adhesion_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.05); //0.1 causes dissasociation, 0.001 is not enough
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.05*M_CELL_FLUCTUATION); //0.1 causes dissasociation

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }
    void TestMeshBasedWithGhostsMonolayerCellSorting()
    {
        // Create a simple mesh
        unsigned num_ghosts = 20;
        HoneycombMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS, num_ghosts);
        MutableMesh<2,2>* p_mesh = generator.GetMesh();

        // Set up cells, one for each non ghost Node
        std::vector<unsigned> location_indices = generator.GetCellLocationIndices();
        std::vector<CellPtr> cells;
        MAKE_PTR(DifferentiatedCellProliferativeType, p_differentiated_type);
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, location_indices.size(), p_differentiated_type);

        // Create cell population
        MeshBasedCellPopulationWithGhostNodes<2> cell_population(*p_mesh, cells, location_indices);
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Mesh");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Create a force law and pass it to the simulation
        MAKE_PTR(DifferentialAdhesionGeneralisedLinearSpringForce<2>, p_differential_adhesion_force);
        p_differential_adhesion_force->SetMeinekeSpringStiffness(50.0);
        p_differential_adhesion_force->SetHomotypicLabelledSpringConstantMultiplier(1.0);
        p_differential_adhesion_force->SetHeterotypicSpringConstantMultiplier(0.1);
        simulator.AddForce(p_differential_adhesion_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.1);
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.1*M_CELL_FLUCTUATION); //0.1 causes dissasociation

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }

    void TestVertexMonolayerCellSorting()
    {
        // Create a simple 2D MutableVertexMesh
        HoneycombVertexMeshGenerator generator(M_NUM_CELLS_ACROSS, M_NUM_CELLS_ACROSS);
        MutableVertexMesh<2,2>* p_mesh = generator.GetMesh();
        p_mesh->SetCellRearrangementThreshold(0.1);

        // Slows things down but can use a larger timestep and diffusion forces
        //p_mesh->SetCheckForInternalIntersections(true);

        // Set up cells, one for each VertexElement
        std::vector<CellPtr> cells;
        boost::shared_ptr<AbstractCellProperty> p_cell_type(CellPropertyRegistry::Instance()->Get<DifferentiatedCellProliferativeType>());
        CellsGenerator<UniformG1GenerationalCellCycleModel, 2> cells_generator;
        cells_generator.GenerateBasicRandom(cells, p_mesh->GetNumElements(), p_cell_type);

        for (unsigned i=0; i<cells.size(); i++)
        {
            // Set a target area rather than setting a growth modifier. (the modifiers don't work correctly as making very long G1 phases)
            cells[i]->GetCellData()->SetItem("target area", 1.0);
        }

        // Create cell population
        VertexBasedCellPopulation<2> cell_population(*p_mesh, cells);

        // Set population to output all data to results files
        cell_population.AddCellWriter<CellIdWriter>();
        cell_population.AddCellWriter<CellMutationStatesWriter>();
        cell_population.AddPopulationWriter<HeterotypicBoundaryLengthWriter>();
        cell_population.AddPopulationWriter<CellPopulationAdjacencyMatrixWriter>();

        // Set up cell-based simulation and output directory
        OffLatticeSimulation<2> simulator(cell_population);
        simulator.SetOutputDirectory("CellSorting/Vertex");

        // Set time step and end time for simulation
        simulator.SetDt(1.0/200.0);
        simulator.SetSamplingTimestepMultiple(200);
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE);

        // Set up force law and pass it to the simulation
        MAKE_PTR(NagaiHondaDifferentialAdhesionForce<2>, p_force);
        p_force->SetNagaiHondaDeformationEnergyParameter(50.0);
        p_force->SetNagaiHondaMembraneSurfaceEnergyParameter(1.0);
        p_force->SetNagaiHondaCellCellAdhesionEnergyParameter(1.0);
        p_force->SetNagaiHondaLabelledCellCellAdhesionEnergyParameter(2.0);
        p_force->SetNagaiHondaLabelledCellLabelledCellAdhesionEnergyParameter(1.0);
        p_force->SetNagaiHondaCellBoundaryAdhesionEnergyParameter(10.0);
        p_force->SetNagaiHondaLabelledCellBoundaryAdhesionEnergyParameter(20.0);
        simulator.AddForce(p_force);

        // Add some noise to avoid local minimum
        MAKE_PTR(RandomMotionForce<2>, p_random_force);
        p_random_force->SetMovementParameter(0.1);
        simulator.AddForce(p_random_force);

        // Run simulation
        simulator.Solve();

        // Now label some cells
        boost::shared_ptr<AbstractCellProperty> p_state(CellPropertyRegistry::Instance()->Get<CellLabel>());
        RandomlyLabelCells(simulator.rGetCellPopulation().rGetCells(), p_state, 0.5);

        // Adjust parameters
        p_random_force->SetMovementParameter(0.1*M_CELL_FLUCTUATION);

        // Run simulation
        simulator.SetEndTime(M_TIME_TO_STEADY_STATE + M_TIME_FOR_SIMULATION);
        simulator.Solve();

        // Check that the same number of cells
        TS_ASSERT_EQUALS(simulator.rGetCellPopulation().GetNumRealCells(), M_NUM_CELLS_ACROSS*M_NUM_CELLS_ACROSS);

        // Test no births or deaths
        TS_ASSERT_EQUALS(simulator.GetNumBirths(), 0u);
        TS_ASSERT_EQUALS(simulator.GetNumDeaths(), 0u);
    }
};

Adhesion Example#

Code overview#

CA#

CP#

OS#

VT#

VM#

Code#

File name TestCellSortingLiteratePaper.hpp#

Adhesion Example

Code overview

CA

CP

OS

VT

VM

Code

File name `TestCellSortingLiteratePaper.hpp`