SimpleWntCellCycleModel.cpp

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#include "SimpleWntCellCycleModel.hpp"
#include "Exception.hpp"
#include "StemCellProliferativeType.hpp"
#include "TransitCellProliferativeType.hpp"
#include "DifferentiatedCellProliferativeType.hpp"
#include "CellLabel.hpp"
#include "WildTypeCellMutationState.hpp"
#include "ApcOneHitCellMutationState.hpp"
#include "ApcTwoHitCellMutationState.hpp"
#include "BetaCateninOneHitCellMutationState.hpp"

SimpleWntCellCycleModel::SimpleWntCellCycleModel()
    : mUseCellProliferativeTypeDependentG1Duration(false),
      mWntStemThreshold(0.8),
      mWntTransitThreshold(0.65),
      mWntLabelledThreshold(0.65)
{
}

SimpleWntCellCycleModel::SimpleWntCellCycleModel(const SimpleWntCellCycleModel& rModel)
   : AbstractSimplePhaseBasedCellCycleModel(rModel),
     mUseCellProliferativeTypeDependentG1Duration(rModel.mUseCellProliferativeTypeDependentG1Duration),
     mWntStemThreshold(rModel.mWntStemThreshold),
     mWntTransitThreshold(rModel.mWntTransitThreshold),
     mWntLabelledThreshold(rModel.mWntLabelledThreshold)
{
    /*
     * Initialize only those member variables defined in this class.
     *
     * The member variables mCurrentCellCyclePhase, mG1Duration,
     * mMinimumGapDuration, mStemCellG1Duration, mTransitCellG1Duration,
     * mSDuration, mG2Duration and mMDuration are initialized in the
     * AbstractPhaseBasedCellCycleModel constructor.
     *
     * The member variables mBirthTime, mReadyToDivide and mDimension
     * are initialized in the AbstractCellCycleModel constructor.
     *
     * Note that mG1Duration and the cell's proliferative type are
     * (re)set as soon as InitialiseDaughterCell() is called on the
     * new cell-cycle model.
     */
}

AbstractCellCycleModel* SimpleWntCellCycleModel::CreateCellCycleModel()
{
    return new SimpleWntCellCycleModel(*this);
}

bool SimpleWntCellCycleModel::GetUseCellProliferativeTypeDependentG1Duration() const
{
    return mUseCellProliferativeTypeDependentG1Duration;
}

void SimpleWntCellCycleModel::SetUseCellProliferativeTypeDependentG1Duration(bool useCellProliferativeTypeDependentG1Duration)
{
    mUseCellProliferativeTypeDependentG1Duration = useCellProliferativeTypeDependentG1Duration;
}

void SimpleWntCellCycleModel::SetG1Duration()
{
    assert(mpCell != nullptr);

    RandomNumberGenerator* p_gen = RandomNumberGenerator::Instance();

    if (mpCell->GetCellProliferativeType()->IsType<StemCellProliferativeType>())
    {
        if (mUseCellProliferativeTypeDependentG1Duration)
        {
            mG1Duration = p_gen->NormalRandomDeviate(GetStemCellG1Duration(), 1.0);
        }
        else
        {
            // Normally stem cells should behave just like transit cells in a Wnt simulation
            mG1Duration = p_gen->NormalRandomDeviate(GetTransitCellG1Duration(), 1.0);
        }
    }
    else if (mpCell->GetCellProliferativeType()->IsType<TransitCellProliferativeType>())
    {
        mG1Duration = p_gen->NormalRandomDeviate(GetTransitCellG1Duration(), 1.0);
    }
    else if (mpCell->GetCellProliferativeType()->IsType<DifferentiatedCellProliferativeType>())
    {
        mG1Duration = DBL_MAX;
    }
    else
    {
        NEVER_REACHED;
    }

    // Check that the normal random deviate has not returned a small or negative G1 duration
    if (mG1Duration < mMinimumGapDuration)
    {
        mG1Duration = mMinimumGapDuration;
    }
}

double SimpleWntCellCycleModel::GetWntLevel() const
{
    assert(mpCell != nullptr);
    double level = 0;

    switch (mDimension)
    {
        case 1:
        {
            const unsigned DIM = 1;
            level = WntConcentration<DIM>::Instance()->GetWntLevel(mpCell);
            break;
        }
        case 2:
        {
            const unsigned DIM = 2;
            level = WntConcentration<DIM>::Instance()->GetWntLevel(mpCell);
            break;
        }
        case 3:
        {
            const unsigned DIM = 3;
            level = WntConcentration<DIM>::Instance()->GetWntLevel(mpCell);
            break;
        }
        default:
            NEVER_REACHED;
    }
    return level;
}

WntConcentrationType SimpleWntCellCycleModel::GetWntType()
{
    WntConcentrationType wnt_type;
    switch (mDimension)
    {
        case 1:
        {
            const unsigned DIM = 1;
            wnt_type = WntConcentration<DIM>::Instance()->GetType();
            break;
        }
        case 2:
        {
            const unsigned DIM = 2;
            wnt_type = WntConcentration<DIM>::Instance()->GetType();
            break;
        }
        case 3:
        {
            const unsigned DIM = 3;
            wnt_type = WntConcentration<DIM>::Instance()->GetType();
            break;
        }
        case UNSIGNED_UNSET:
        {
            // If you trip this you have tried to use a simulation without setting the dimension.
            NEVER_REACHED;
        }
        default:
            NEVER_REACHED;
    }
    return wnt_type;
}

void SimpleWntCellCycleModel::UpdateCellCyclePhase()
{
    // The cell can divide if the Wnt concentration >= wnt_division_threshold
    double wnt_division_threshold = DBL_MAX;

    // Set up under what level of Wnt stimulus a cell will divide
    if (mpCell->GetMutationState()->IsType<WildTypeCellMutationState>())
    {
        wnt_division_threshold = mWntTransitThreshold;
    }
    else if (mpCell->GetMutationState()->IsType<ApcOneHitCellMutationState>())
    {
        // should be less than healthy values
        wnt_division_threshold = 0.77*mWntTransitThreshold;
    }
    else if (mpCell->GetMutationState()->IsType<BetaCateninOneHitCellMutationState>())
    {
        // less than above value
        wnt_division_threshold = 0.155*mWntTransitThreshold;
    }
    else if (mpCell->GetMutationState()->IsType<ApcTwoHitCellMutationState>())
    {
        // should be zero (no Wnt-dependence)
        wnt_division_threshold = 0.0;
    }
    else
    {
        NEVER_REACHED;
    }

    if (mpCell->HasCellProperty<CellLabel>())
    {
        wnt_division_threshold = mWntLabelledThreshold;
    }

    double wnt_level = GetWntLevel();
    WntConcentrationType wnt_type = GetWntType();

    // Set the cell type to TransitCellProliferativeType if the Wnt stimulus exceeds wnt_division_threshold
    if (wnt_level >= wnt_division_threshold)
    {
        // For a RADIAL Wnt type, override the cell type to StemCellProliferativeType if the Wnt stimulus exceeds a higher threshold
        if ((wnt_type == RADIAL) && (wnt_level > mWntStemThreshold))
        {
            /*
             * This method is usually called within a CellBasedSimulation, after the CellPopulation
             * has called CellPropertyRegistry::TakeOwnership(). This means that were we to call
             * CellPropertyRegistry::Instance() here when setting the CellProliferativeType, we
             * would be creating a new CellPropertyRegistry. In this case the cell proliferative
             * type counts, as returned by AbstractCellPopulation::GetCellProliferativeTypeCount(),
             * would be incorrect. We must therefore access the CellProliferativeType via the cell's
             * CellPropertyCollection.
             */
            boost::shared_ptr<AbstractCellProperty> p_stem_type =
                mpCell->rGetCellPropertyCollection().GetCellPropertyRegistry()->Get<StemCellProliferativeType>();
            mpCell->SetCellProliferativeType(p_stem_type);
        }
        else
        {
            boost::shared_ptr<AbstractCellProperty> p_transit_type =
                mpCell->rGetCellPropertyCollection().GetCellPropertyRegistry()->Get<TransitCellProliferativeType>();
            mpCell->SetCellProliferativeType(p_transit_type);
        }
    }
    else
    {
        // The cell is set to have DifferentiatedCellProliferativeType and so in G0 phase
        boost::shared_ptr<AbstractCellProperty> p_diff_type =
            mpCell->rGetCellPropertyCollection().GetCellPropertyRegistry()->Get<DifferentiatedCellProliferativeType>();
        mpCell->SetCellProliferativeType(p_diff_type);
    }
    AbstractSimplePhaseBasedCellCycleModel::UpdateCellCyclePhase();
}

void SimpleWntCellCycleModel::InitialiseDaughterCell()
{
    WntConcentrationType wnt_type = GetWntType();

    if (wnt_type == RADIAL)
    {
        boost::shared_ptr<AbstractCellProperty> p_transit_type =
            mpCell->rGetCellPropertyCollection().GetCellPropertyRegistry()->Get<TransitCellProliferativeType>();
        mpCell->SetCellProliferativeType(p_transit_type);
    }

    AbstractSimplePhaseBasedCellCycleModel::InitialiseDaughterCell();
}

bool SimpleWntCellCycleModel::CanCellTerminallyDifferentiate()
{
    return false;
}

double SimpleWntCellCycleModel::GetWntStemThreshold() const
{
    return mWntStemThreshold;
}

void SimpleWntCellCycleModel::SetWntStemThreshold(double wntStemThreshold)
{
    assert(wntStemThreshold <= 1.0);
    assert(wntStemThreshold >= 0.0);
    mWntStemThreshold = wntStemThreshold;
}

double SimpleWntCellCycleModel::GetWntTransitThreshold() const
{
    return mWntTransitThreshold;
}

void SimpleWntCellCycleModel::SetWntTransitThreshold(double wntTransitThreshold)
{
    //assert(wntTransitThreshold <= 1.0);
    //assert(wntTransitThreshold >= 0.0);
    mWntTransitThreshold = wntTransitThreshold;
}

double SimpleWntCellCycleModel::GetWntLabelledThreshold() const
{
    return mWntLabelledThreshold;
}

void SimpleWntCellCycleModel::SetWntLabelledThreshold(double wntLabelledThreshold)
{
//    assert(wntLabelledThreshold <= 1.0);
//    assert(wntLabelledThreshold >= 0.0);
    mWntLabelledThreshold = wntLabelledThreshold;
}

void SimpleWntCellCycleModel::OutputCellCycleModelParameters(out_stream& rParamsFile)
{
    *rParamsFile << "\t\t\t<UseCellProliferativeTypeDependentG1Duration>" << mUseCellProliferativeTypeDependentG1Duration << "</UseCellProliferativeTypeDependentG1Duration>\n";
    *rParamsFile << "\t\t\t<WntStemThreshold>" << mWntStemThreshold << "</WntStemThreshold>\n";
    *rParamsFile << "\t\t\t<WntTransitThreshold>" << mWntTransitThreshold << "</WntTransitThreshold>\n";
    *rParamsFile << "\t\t\t<WntLabelledThreshold>" << mWntLabelledThreshold << "</WntLabelledThreshold>\n";

    // Call method on direct parent class
    AbstractSimplePhaseBasedCellCycleModel::OutputCellCycleModelParameters(rParamsFile);
}

// Serialization for Boost >= 1.36
#include "SerializationExportWrapperForCpp.hpp"
CHASTE_CLASS_EXPORT(SimpleWntCellCycleModel)