Human iPSC Wildtype Colony Growth
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Introduction
Human induced pluripotent stem cells (hiPSCs) can be grown in cell culture where they self-organize spatial patterns. Libby et al. have employed inducible CRISPR interference-driven genetic perturbations to modulate mechanical cell properties like cell-cell adhesion and cortical tension. Cells with induced perturbations were labelled by mCherry, revealing emergent spatial patterns including the well-mixed, multi-island, and bullseye patterns.
The multi-cellular model allowed to optimize parameter values in silico (and corresponding to CRISPR-based modulations of the mechanical cell properties) in order to obtain a selected target pattern. The in silico predicted experimental parameters were then indeed found to generate the desired patterns in vitro. This proposes a strategy for controlled spatio-temporal patterning in tissue engineering. See also the two other, related models by Libby et al.
Description
- Units in the model are $[\text{space}] = \mathrm{\mu m}$, $[\text{time}] = \mathrm{hours}$.
- Parameter values were fitted to in vitro cell culture experiments of hiPSC colony growth.
- In this CPM-based model, the primary determinant of global patterning is differential adhesion. However, other cellular behaviors such as persistent motion, contact-inhibited migration (or lack thereof), cell cortex rigidity, and (optional) the tendency of peripheral cells to be more migratory are represented in this model.
- Initial conditions: 2 cell types for labeling purposes, random initial positions, 100 total cells densely clustered
- Constraints: cell size, cortex stiffness, cell-cell adhesion strength, cell-media adhesion (at colony borders) are derived from literature and experiments.
- The published model file was originally developed with Morpheus version 1.9.1 and is provided by the authors (Demarcus Briers, Iman Haghighi, David Joy and Ashley Libby) together with a docker container, data analysis pipeline and parameter optimization pipeline at Demarcus Briers' Git repo.
- The new model file provided below has been updated (solver naming, added
ctall_medium_adhesion_init = 0inGlobalto ease initialization ofCellTypes, added reference and links to description) such that it works with Morpheus version 2.2.2 and later and reproduces the original results.
Results
This model reproduces the pure wildtype cell culture simulation as published in Video S2 of Libby et al. The spatio-temporal pattern matches the experiment (random mCherry labelling without further perturbations) as published in Video S1 of Libby et al. The following figure shows a snapshot of the simulation state at $96\ \mathrm h$ of $120\ \mathrm h$.
Reference
This model is described in the peer-reviewed publication:
A. R. G. Libby, D. Briers, I. Haghighi, D. A. Joy, B. R. Conklin, C. Belta, T. C. McDevitt: Automated Design of Pluripotent Stem Cell Self-Organization. Cell Systems 9 (5): 483–495, 2019.
Model
model.xml
XML Preview
<?xml version='1.0'?>
<MorpheusModel version="4">
<Description>
<Title>Libby2019</Title>
<Details>Full title:Human iPSC wildtype colony growth.
Date: 31.05.2021
Authors: A. R.G. Libby, D. Briers, I. Haghighi, D. A. Joy, B. R. Conklin, C. Belta, T. C. McDevitt
Curators: Lutz Brusch (lutz.brusch@tu-dresden.de)
Software: Morpheus (open-source), download from https://morpheus.gitlab.io
ModelID: https://identifiers.org/morpheus/M7671
Reference:This model is described in the peer-reviewed publication
A. R.G. Libby, D. Briers, I. Haghighi, D. A. Joy, B. R. Conklin, C. Belta, T. C. McDevitt.
Automated Design of Pluripotent Stem Cell Self-Organization.
Cell Systems 9(5): 483–495, 2019.
</Details>
</Description>
<Global>
<Variable value="-100" symbol="ct1_adhesion"/>
<Variable value="-100" symbol="ct2_adhesion"/>
<Variable value="max(ct1_adhesion,ct2_adhesion)" symbol="ct1_ct2"/>
<Constant value="0" symbol="ctall_medium_adhesion_init"/>
<Variable value="ctall_medium_adhesion_init" symbol="ctall_medium_adhesion"/>
<Variable value="0" symbol="ct1_perturbation_time" name="time_of_knockout_initiation_ct1_adhesion"/>
<Constant value="-100" symbol="adhesion_init_ct1"/>
<Variable value="-100" symbol="ct1_adhesion_weak"/>
<Variable value="1.12" symbol="ct1_membraneElasticity_init"/>
<Variable value="1.12" symbol="ct1_membraneElasticity"/>
<Variable value="1.12" symbol="ct1_membraneElasticity_final"/>
<Variable value="1.32" symbol="ct1_membraneElasticity_edge_init"/>
<Variable value="1.32" symbol="ct1_membraneElasticity_edge"/>
<Variable value="1.32" symbol="ct1_membraneElasticity_final_edge"/>
<Variable value="48.28" symbol="ct1_k_half_hours"/>
<Variable value="5.0" symbol="ct1_hill_n" name=""/>
<Variable value="137" symbol="ct1_area_init"/>
<Variable value="137" symbol="ct1_area" name=""/>
<Variable value="137" symbol="ct1_area_final" name=""/>
<Variable value="34.03" symbol="ct1_area_final_sd"/>
<Variable value="177" symbol="ct1_area_edge_init"/>
<Variable value="177" symbol="ct1_area_edge" name=""/>
<Variable value="177" symbol="ct1_area_edge_final" name=""/>
<Variable value="49.66" symbol="ct1_area_edge_final_sd"/>
<Variable value="20" symbol="ct1_generation_time_init"/>
<Variable value="20" symbol="ct1_generation_time_final"/>
<Variable value="20" symbol="ct1_generation_time"/>
<Variable value="0.5" symbol="ct1_membrane_str_init"/>
<Variable value="0.5" symbol="ct1_membrane_str_final"/>
<Variable value="0.5" symbol="ct1_membrane_str"/>
<Variable value="9" symbol="ct1_persistent_motion_str_init"/>
<Variable value="9" symbol="ct1_persistent_motion_str_final"/>
<Variable value="9" symbol="ct1_persistent_motion"/>
<Variable value="0" symbol="ct2_perturbation_time" name="time_of_knockout_initiation_ct2_adhesion"/>
<Constant value="-100" symbol="adhesion_init_ct2"/>
<Variable value="-100" symbol="ct2_adhesion_weak"/>
<Variable value="1.12" symbol="ct2_membraneElasticity_init"/>
<Variable value="1.12" symbol="ct2_membraneElasticity"/>
<Variable value="1.12" symbol="ct2_membraneElasticity_final"/>
<Variable value="1.32" symbol="ct2_membraneElasticity_edge_init"/>
<Variable value="1.32" symbol="ct2_membraneElasticity_edge"/>
<Variable value="1.32" symbol="ct2_membraneElasticity_final_edge"/>
<Variable value="48.28" symbol="ct2_k_half_hours"/>
<Variable value="5.0" symbol="ct2_hill_n"/>
<Variable value="137" symbol="ct2_area_init"/>
<Variable value="137" symbol="ct2_area"/>
<Variable value="34.03" symbol="ct2_area_final_sd"/>
<Variable value="137" symbol="ct2_area_final"/>
<Variable value="177" symbol="ct2_area_edge_init"/>
<Variable value="177" symbol="ct2_area_edge"/>
<Variable value="177" symbol="ct2_area_edge_final"/>
<Variable value="49.66" symbol="ct2_area_edge_final_sd"/>
<Variable value="20" symbol="ct2_generation_time_init"/>
<Variable value="20" symbol="ct2_generation_time_final"/>
<Variable value="20" symbol="ct2_generation_time"/>
<Variable value="0.5" symbol="ct2_membrane_str_init"/>
<Variable value="0.5" symbol="ct2_membrane_str_final"/>
<Variable value="0.5" symbol="ct2_membrane_str"/>
<Variable value="9" symbol="ct2_persistent_motion_str_init"/>
<Variable value="9" symbol="ct2_persistent_motion_str_final"/>
<Variable value="9" symbol="ct2_persistent_motion"/>
<System time-step="0.1" solver="Euler [fixed, O(1)]" name="ct1_mechanics_updater">
<Rule symbol-ref="ct1_adhesion">
<Expression>if(time < burn_in_time, adhesion_init_ct1,
if(time > ct1_perturbation_time
and ct1_adhesion >= adhesion_init_ct1
and ct1_adhesion <= ct1_adhesion_weak,
(1.0 / (1.0 + (pow(((time-ct1_perturbation_time)/ct1_k_half_hours),ct1_hill_n))))* (adhesion_init_ct1-ct1_adhesion_weak) + ct1_adhesion_weak,
if(time <= ct1_perturbation_time,adhesion_init_ct1,ct1_adhesion_weak)
))</Expression>
</Rule>
<Rule symbol-ref="ct1_membraneElasticity">
<Expression>if(time < burn_in_time,ct1_membraneElasticity_init,
if(time > ct1_perturbation_time
and ct1_membraneElasticity >= ct1_membraneElasticity_init
and ct1_membraneElasticity <= ct1_membraneElasticity_final,
(1.0 / (1.0 + (pow(((time-ct1_perturbation_time)/ct1_k_half_hours),ct1_hill_n))))*(ct1_membraneElasticity_init-ct1_membraneElasticity_final) + ct1_membraneElasticity_final,
if(time <= ct1_perturbation_time,ct1_membraneElasticity_init,ct1_membraneElasticity_final)
))</Expression>
</Rule>
<Rule symbol-ref="ct1_membraneElasticity_edge">
<Expression>if(time < burn_in_time,ct1_membraneElasticity_edge_init,
if(time > ct1_perturbation_time
and ct1_membraneElasticity_edge >= ct1_membraneElasticity_edge_init
and ct1_membraneElasticity_edge <= ct1_membraneElasticity_final_edge,
(1.0 / (1.0 + (pow(((time-ct1_perturbation_time)/ct1_k_half_hours),ct1_hill_n))))*(ct1_membraneElasticity_edge_init-ct1_membraneElasticity_final_edge) + ct1_membraneElasticity_final_edge,
if(time <= ct1_perturbation_time,ct1_membraneElasticity_edge_init,ct1_membraneElasticity_final_edge)
))</Expression>
</Rule>
<Rule symbol-ref="ct1_area">
<Expression>if(time >burn_in_time,ct1_area_init,
if( (ct1_area_init < ct1_area_final)
and ct1_area < ct1_area_final,
ct1_area_init +
(ct1_area_final-ct1_area_init)*
((time-ct1_perturbation_time)/96),
ct1_area_final)
)</Expression>
</Rule>
<Rule symbol-ref="ct1_area_edge">
<Expression>if(time < burn_in_time,ct1_area_edge_init,
if((ct1_area_edge_init < ct1_area_edge_final)
and ct1_area_edge < ct1_area_edge_final,
ct1_area_edge_init +
(ct1_area_edge_final-ct1_area_edge_init)*
((time-ct1_perturbation_time)/96),
ct1_area_edge_final)
)
</Expression>
</Rule>
<Rule symbol-ref="ct1_generation_time">
<Expression>if(time < burn_in_time, ct1_generation_time_init,
if(time > ct1_perturbation_time,
(1.0 / (1.0 + (pow(((time-ct1_perturbation_time)/ct1_k_half_hours),ct1_hill_n))))* (ct1_generation_time_init-ct1_generation_time_final) + ct1_generation_time_final,
if(time <= ct1_perturbation_time,ct1_generation_time_init,ct1_generation_time_final)
))
</Expression>
</Rule>
<Rule symbol-ref="ct1_membrane_str">
<Expression>if(time < burn_in_time, ct1_membrane_str_init,
if(time > ct1_perturbation_time
and ct1_membrane_str >= ct1_membrane_str_init
and ct1_membrane_str <= ct1_membrane_str_final,
(1.0 / (1.0 + (pow(((time-ct1_perturbation_time)/ct1_k_half_hours),ct1_hill_n))))* (ct1_membrane_str_init-ct1_membrane_str_final) + ct1_membrane_str_final,
if(time <= ct1_perturbation_time,ct1_membrane_str_init,ct1_membrane_str_final)
))</Expression>
</Rule>
</System>
<System time-step="0.1" solver="Euler [fixed, O(1)]" name="ct2_mechanics_updater">
<Rule symbol-ref="ct2_adhesion">
<Expression>if(time < burn_in_time,adhesion_init_ct2,
if(time > ct2_perturbation_time
and ct2_adhesion >= adhesion_init_ct2
and ct2_adhesion <= ct2_adhesion_weak,
(1.0 / (1.0 + (pow(((time-ct2_perturbation_time)/ct2_k_half_hours),ct2_hill_n))))*(adhesion_init_ct2-ct2_adhesion_weak) + ct2_adhesion_weak,
if(time <= ct2_perturbation_time,adhesion_init_ct2,ct2_adhesion_weak)
))</Expression>
</Rule>
<Rule symbol-ref="ct2_membraneElasticity">
<Expression>if(time < burn_in_time,ct2_membraneElasticity_init,
if(time > ct2_perturbation_time
and ct2_membraneElasticity >= ct2_membraneElasticity_init
and ct2_membraneElasticity <= ct2_membraneElasticity_final,
(1.0 / (1.0 + (pow(((time-ct2_perturbation_time)/ct2_k_half_hours),ct2_hill_n))))*
(ct2_membraneElasticity_init-ct2_membraneElasticity_final) + ct2_membraneElasticity_final,
if(time <= ct2_perturbation_time,ct2_membraneElasticity_init,ct2_membraneElasticity_final)
))</Expression>
</Rule>
<Rule symbol-ref="ct2_membraneElasticity_edge">
<Expression>if(time < burn_in_time,ct2_membraneElasticity_edge_init,
if(time > ct2_perturbation_time
and ct2_membraneElasticity_edge >= ct2_membraneElasticity_edge_init
and ct2_membraneElasticity_edge <= ct2_membraneElasticity_final_edge,
(1.0 / (1.0 + (pow(((time-ct2_perturbation_time)/ct2_k_half_hours),ct2_hill_n))))*(ct2_membraneElasticity_edge_init-ct2_membraneElasticity_final_edge) + ct2_membraneElasticity_final_edge,
if(time <= ct2_perturbation_time,ct2_membraneElasticity_edge_init,ct2_membraneElasticity_final_edge)
))</Expression>
</Rule>
<Rule symbol-ref="ct2_area">
<Expression>if(time < burn_in_time,ct2_area_init,
if( (ct2_area_init < ct2_area_final)
and ct2_area < ct2_area_final,
ct2_area_init + (ct2_area_final-ct2_area_init)*
((time-ct2_perturbation_time)/96),
ct2_area_final)
) </Expression>
</Rule>
<Rule symbol-ref="ct2_area_edge">
<Expression>if(time < burn_in_time,ct2_area_edge_init,
if( (ct2_area_edge_init < ct2_area_edge_final)
and ct2_area_edge < ct2_area_edge_final,
ct2_area_edge_init +
(ct2_area_edge_final-ct2_area_edge_init)*
((time-ct2_perturbation_time)/96),
ct2_area_edge_final)
)</Expression>
</Rule>
<Rule symbol-ref="ct2_generation_time">
<Expression>if(time < burn_in_time, ct2_generation_time_init,
if(time > ct2_perturbation_time,
(1.0 / (1.0 + (pow(((time-ct2_perturbation_time)/ct2_k_half_hours),ct2_hill_n))))* (ct2_generation_time_init-ct2_generation_time_final) + ct2_generation_time_final,
if(time <= ct2_perturbation_time,ct2_generation_time_init,ct2_generation_time_final)
))
</Expression>
</Rule>
<Rule symbol-ref="ct2_membrane_str">
<Expression>if(time < burn_in_time, ct2_membrane_str_init,
if(time > ct2_perturbation_time
and ct2_membrane_str >= ct2_membrane_str_init
and ct2_membrane_str <= ct2_membrane_str_final,
(1.0 / (1.0 + (pow(((time-ct2_perturbation_time)/ct1_k_half_hours),ct2_hill_n))))* (ct2_membrane_str_init-ct2_membrane_str_final) + ct2_membrane_str_final,
if(time <= ct2_perturbation_time,ct2_membrane_str_init,ct2_membrane_str_final)
))</Expression>
</Rule>
</System>
<System time-step="0.1" solver="Euler [fixed, O(1)]" name="adhesion_ct1_ct2">
<Rule symbol-ref="ct1_ct2">
<Expression>max(ct1_adhesion,ct2_adhesion)</Expression>
</Rule>
</System>
<Constant value="0" symbol="wt_offset_x"/>
<Constant value="0" symbol="wt_offset_y"/>
<Constant value="0" symbol="inhibited_offset_x"/>
<Constant value="0" symbol="inhibited_offset_y"/>
<Field value="0" symbol="U" name="chemoattractant">
<Diffusion rate="0"/>
</Field>
<!-- <Disabled>
<System time-step="1" solver="Euler [fixed, O(1)]">
<DiffEqn symbol-ref="U">
<Expression>p-degp*U</Expression>
</DiffEqn>
</System>
</Disabled>
-->
<!-- <Disabled>
<Constant value="0.003" symbol="cell_density"/>
</Disabled>
-->
<!-- <Disabled>
<Field value="0" symbol="protrusionMemory">
<Diffusion rate="0.0"/>
</Field>
</Disabled>
-->
<Variable value="50" symbol="num_cells_ct2"/>
<Variable value="100-num_cells_ct2" symbol="num_cells_ct1"/>
<Variable value="1" symbol="avgMediaNeighborLength" name="percent_membrane_bordeing_media"/>
<Variable value="5" symbol="burn_in_time"/>
</Global>
<Space>
<Lattice class="square">
<Size value="1200,1200,0" symbol="lattice"/>
<BoundaryConditions>
<Condition boundary="x" type="constant"/>
<Condition boundary="y" type="constant"/>
</BoundaryConditions>
<Neighborhood>
<Order>4</Order>
</Neighborhood>
</Lattice>
<SpaceSymbol symbol="space"/>
</Space>
<Time>
<StartTime value="0"/>
<StopTime value="120" symbol="hours"/>
<TimeSymbol symbol="time"/>
<RandomSeed value="43263"/>
</Time>
<CellTypes>
<CellType name="ct1" class="biological">
<Property value="0" symbol="d" name="divisions"/>
<Property value="0" symbol="c" name="color"/>
<Property value="ct1_generation_time" symbol="dt" name="generationTime"/>
<Property value="0.0" symbol="dc" name="division_time_counter"/>
<Property value="1.0" symbol="cell" name="cell (for counting)"/>
<Property value="ct1_adhesion" symbol="cadherin"/>
<Property value="ct1_ct2" symbol="ct1_ct2_adhesion"/>
<!-- <Disabled>
<Property value="0.5" symbol="percentDaughterVolume" name="percentVolume2DaughterCell"/>
</Disabled>
-->
<!-- <Disabled>
<Constant value="32.0" symbol="maxTargetArea"/>
</Disabled>
-->
<!-- <Disabled>
<Property value="0.5*maxTargetArea/dt" symbol="cellVolumeIncrement"/>
</Disabled>
-->
<Property value="ct1_area" symbol="targetArea"/>
<Property value="ct1_membraneElasticity" symbol="targetSurface"/>
<VolumeConstraint strength="1.0" target="targetArea"/>
<SurfaceConstraint mode="aspherity" strength="ct1_membrane_str" target="targetSurface"/>
<PropertyVector value="0.0, 0.0, 0.0" symbol="dv" name="direction_vector"/>
<PersistentMotion decay-time="0.003" protrusion="true" strength="9"/>
<!-- <Disabled>
<Event trigger="when true" name="partitionCell">
<Condition>dc == (dt-1)</Condition>
<Rule symbol-ref="percentDaughterVolume">
<Expression>rand_uni(0.45,0.55)</Expression>
</Rule>
</Event>
</Disabled>
-->
<CellDivision division-plane="minor" daughterID="daughter">
<Condition>dc >= dt</Condition>
<Triggers name="">
<Rule symbol-ref="dc">
<Expression>0</Expression>
</Rule>
<!-- <Disabled>
<Rule symbol-ref="targetArea">
<Expression>if( daughter == 1,
percentDaughterVolume*maxTargetArea,
(1-percentDaughterVolume)*maxTargetArea )</Expression>
</Rule>
</Disabled>
-->
</Triggers>
</CellDivision>
<System time-step="1" solver="Euler [fixed, O(1)]" name="cell_state_updater">
<Rule symbol-ref="dc">
<Expression>dc+1</Expression>
</Rule>
<!-- <Disabled>
<Rule symbol-ref="c">
<Expression>if(isEdgeCell > 0,2,0)</Expression>
</Rule>
</Disabled>
-->
<!-- <Disabled>
<Rule symbol-ref="targetArea">
<Expression>if((time-ct1_perturbation_time) > ct1_k_half_hours,
if(isEdgeCell > 0,
cell_area_edge_final,
cell_area_final),
if(isEdgeCell > 0,
cell_area_edge,
cell_area)
)</Expression>
</Rule>
</Disabled>
-->
<Rule symbol-ref="targetSurface">
<Expression>if(isEdgeCell > 0,
ct1_membraneElasticity_edge,
ct1_membraneElasticity)</Expression>
</Rule>
</System>
<!-- <Disabled>
<PropertyVector value="0.0, 0.0, 0.0" symbol="displacement"/>
</Disabled>
-->
<!-- <Disabled>
<MotilityReporter time-step="1">
<Displacement symbol-ref="displacement"/>
</MotilityReporter>
</Disabled>
-->
<Property value="10" symbol="p"/>
<Chemotaxis field="U" retraction="true" strength="3" contact-inhibition="true"/>
<Constant value="0.9" symbol="degp"/>
<!-- <Disabled>
<Protrusion maximum="10" field="protrusionMemory" strength="1"/>
</Disabled>
-->
<Property value="0" symbol="isEdgeCell"/>
<NeighborhoodReporter>
<Input scaling="cell" value="cell.type == celltype.medium.id"/>
<Output symbol-ref="isEdgeCell" mapping="sum"/>
</NeighborhoodReporter>
<Property value="ctall_medium_adhesion_init" symbol="ctall_medium_adhesion"/>
<Property value="0" symbol="cell_area_final"/>
<Property value="0" symbol="cell_area_edge_final"/>
</CellType>
<CellType name="ct2" class="biological">
<Property value="0" symbol="d" name="divisions"/>
<Property value="1" symbol="c" name="color"/>
<Property value="1.0" symbol="cell" name="cell (for counting)"/>
<Property value="ct2_generation_time" symbol="dt" name="generationTime"/>
<Property value="0.0" symbol="dc" name="division_time_counter"/>
<Property value="ct2_adhesion" symbol="cadherin" name="global_cadherin_inhibitedpop"/>
<Property value="ct1_ct2" symbol="ct1_ct2_adhesion"/>
<Property value="ctall_medium_adhesion_init" symbol="ctall_medium_adhesion"/>
<Property value="0" symbol="avgLikeNeighborCount"/>
<Property value="0" symbol="avgLikeNeighborLength"/>
<Property value="ct2_area" symbol="targetArea"/>
<Property value="ct2_membraneElasticity" symbol="targetSurface"/>
<VolumeConstraint strength="1" target="targetArea"/>
<SurfaceConstraint mode="aspherity" strength="ct2_membrane_str" target="targetSurface"/>
<PropertyVector value="0.0, 0.0, 0.0" symbol="dv" name="direction_vector"/>
<PersistentMotion decay-time="0.003" protrusion="true" strength="9"/>
<CellDivision division-plane="major" daughterID="daughter">
<Condition>dc >= dt</Condition>
<Triggers name="">
<Rule symbol-ref="dc">
<Expression>0</Expression>
</Rule>
<!-- <Disabled>
<Rule symbol-ref="targetArea">
<Expression>if( daughter == 1,
percentDaughterVolume*maxTargetArea,
(1-percentDaughterVolume)*maxTargetArea )</Expression>
</Rule>
</Disabled>
-->
</Triggers>
</CellDivision>
<System time-step="1" solver="Euler [fixed, O(1)]" name="cell_state_updater">
<Rule symbol-ref="dc">
<Expression>dc+1</Expression>
</Rule>
<!-- <Disabled>
<Rule symbol-ref="c">
<Expression>if(isEdgeCell > 0,2,1)</Expression>
</Rule>
</Disabled>
-->
<Rule symbol-ref="targetArea" name="CellGrowth">
<Expression>if(isEdgeCell > 0,ct2_area_edge,ct2_area)</Expression>
</Rule>
<Rule symbol-ref="targetSurface">
<Expression>if(isEdgeCell > 0,ct2_membraneElasticity_edge,ct2_membraneElasticity)</Expression>
</Rule>
<!-- <Disabled>
<Rule symbol-ref="ctall_medium_adhesion" name="peripheral_cell_migration">
<Expression>if(avgMediaNeighborLength > 0.35,max(cadherin,ct1_ct2_adhesion)/2,0)</Expression>
</Rule>
</Disabled>
-->
</System>
<!-- <Disabled>
<PropertyVector value="0.0, 0.0, 0.0" symbol="displacement"/>
</Disabled>
-->
<!-- <Disabled>
<MotilityReporter time-step="1">
<Displacement symbol-ref="displacement"/>
</MotilityReporter>
</Disabled>
-->
<Property value="10" symbol="p"/>
<Constant value="0.9" symbol="degp"/>
<Chemotaxis field="U" retraction="true" strength="3" contact-inhibition="true"/>
<!-- <Disabled>
<Protrusion maximum="10" field="protrusionMemory" strength="1"/>
</Disabled>
-->
<Property value="0" symbol="isEdgeCell"/>
<NeighborhoodReporter>
<Input scaling="cell" value="cell.type == celltype.medium.id"/>
<Output symbol-ref="isEdgeCell" mapping="sum"/>
</NeighborhoodReporter>
<Property value="0" symbol="cell_area_final"/>
<Property value="0" symbol="cell_area_edge_final"/>
</CellType>
<!-- <Disabled>
<CellType name="collagen" class="biological">
<Property value="0" symbol="d" name="divisions"/>
<Property value="2" symbol="c" name="color"/>
<Property value="1.0" symbol="cell" name="cell (for counting)"/>
<Disabled>
<Property value="20" symbol="dt" name="generationTime"/>
</Disabled>
<Property value="0.0" symbol="dc" name="division_time_counter"/>
<Property value="10" symbol="targetArea"/>
<Property value="2" symbol="cadherin" name="global_cadherin_inhibitedpop"/>
<Disabled>
<Property value="0" symbol="avgLikeNeighborCount"/>
</Disabled>
<Disabled>
<Property value="0" symbol="avgLikeNeighborLength"/>
</Disabled>
<VolumeConstraint strength="1" target="targetArea"/>
<PropertyVector value="0.0, 0.0, 0.0" symbol="dv" name="direction_vector"/>
<Disabled>
<CellDivision division-plane="major" daughterID="daughter">
<Condition>dc >= dt</Condition>
<Triggers name="">
<Rule symbol-ref="dc">
<Expression>0</Expression>
</Rule>
<Disabled>
<Rule symbol-ref="targetArea">
<Expression>if( daughter == 1,
percentDaughterVolume*maxTargetArea,
(1-percentDaughterVolume)*maxTargetArea )</Expression>
</Rule>
</Disabled>
</Triggers>
</CellDivision>
</Disabled>
<Property value="2" symbol="ct1_ct2_adhesion"/>
<Property value="0.10" symbol="p"/>
<Disabled>
<Chemotaxis field="U" retraction="true" strength="c" contact-inhibition="false"/>
</Disabled>
<FreezeMotion>
<Condition>time >=5</Condition>
</FreezeMotion>
</CellType>
</Disabled>
-->
<CellType name="medium" class="medium">
<Property value="ctall_medium_adhesion" symbol="cadherin"/>
<Property value="0" symbol="avgLikeNeighborCount"/>
<Property value="0" symbol="avgLikeNeighborLength"/>
<Property value="0" symbol="p"/>
<!-- <Disabled>
<Property value="0" symbol="dc"/>
</Disabled>
-->
<Constant value="0.0" symbol="degp"/>
</CellType>
<!-- <Disabled>
<CellType name="sisterColony" class="biological">
<Property value="0" symbol="d" name="divisions"/>
<Property value="3" symbol="c" name="color"/>
<Property value="1.0" symbol="cell" name="cell (for counting)"/>
<Disabled>
<Property value="20" symbol="dt" name="generationTime"/>
</Disabled>
<Property value="0.0" symbol="dc" name="division_time_counter"/>
<Property value="500" symbol="targetArea"/>
<Property value="2" symbol="cadherin" name="global_cadherin_inhibitedpop"/>
<Disabled>
<Property value="0" symbol="avgLikeNeighborCount"/>
</Disabled>
<Disabled>
<Property value="0" symbol="avgLikeNeighborLength"/>
</Disabled>
<VolumeConstraint strength="1" target="targetArea"/>
<PropertyVector value="0.0, 0.0, 0.0" symbol="dv" name="direction_vector"/>
<Disabled>
<CellDivision division-plane="major" daughterID="daughter">
<Condition>dc >= dt</Condition>
<Triggers name="">
<Rule symbol-ref="dc">
<Expression>0</Expression>
</Rule>
<Disabled>
<Rule symbol-ref="targetArea">
<Expression>if( daughter == 1,
percentDaughterVolume*maxTargetArea,
(1-percentDaughterVolume)*maxTargetArea )</Expression>
</Rule>
</Disabled>
</Triggers>
</CellDivision>
</Disabled>
<Property value="2" symbol="ct1_ct2_adhesion"/>
<Property value="500" symbol="p"/>
<Disabled>
<Chemotaxis field="U" retraction="true" strength="c" contact-inhibition="false"/>
</Disabled>
<Disabled>
<FreezeMotion>
<Condition>time >=5</Condition>
</FreezeMotion>
</Disabled>
<SurfaceConstraint mode="aspherity" strength="1" target="0.5"/>
</CellType>
</Disabled>
-->
</CellTypes>
<CPM>
<Interaction default="0">
<Contact value="0" type1="ct1" type2="medium">
<HomophilicAdhesion adhesive="ctall_medium_adhesion" strength="1"/>
</Contact>
<Contact value="0" type1="ct2" type2="medium">
<HomophilicAdhesion adhesive="ctall_medium_adhesion" strength="1"/>
</Contact>
<Contact value="0" type1="ct1" type2="ct1">
<HomophilicAdhesion adhesive="cadherin" strength="1"/>
</Contact>
<Contact value="0" type1="ct1" type2="ct2">
<HomophilicAdhesion adhesive="ct1_ct2" strength="1"/>
</Contact>
<Contact value="0" type1="ct2" type2="ct2">
<HomophilicAdhesion adhesive="cadherin" strength="1"/>
</Contact>
</Interaction>
<MonteCarloSampler stepper="edgelist">
<MCSDuration value="0.03"/>
<Neighborhood>
<Order>4</Order>
</Neighborhood>
<MetropolisKinetics yield="0.1" temperature="10"/>
</MonteCarloSampler>
<ShapeSurface scaling="norm">
<Neighborhood>
<Order>1</Order>
</Neighborhood>
</ShapeSurface>
</CPM>
<CellPopulations>
<Population size="1" type="ct1" name="cell_type_1">
<!-- <Disabled>
<InitCircle mode="random" number-of-cells="75" random_displacement="0.3*lattice.x">
<Dimensions center="lattice.x/2,lattice.y/2,0" radius="20"/>
</InitCircle>
</Disabled>
-->
<InitProperty symbol-ref="dc">
<Expression>rand_uni(0,dt)</Expression>
</InitProperty>
<InitRectangle mode="regular" random-offset="10" number-of-cells="num_cells_ct1">
<Dimensions size="60,20,0" origin="(lattice.x/2)+wt_offset_x,(lattice.y/2)+wt_offset_y,0"/>
</InitRectangle>
<!-- <Disabled>
<InitProperty symbol-ref="cell_area_final">
<Expression>rand_norm(ct1_area_final,ct1_area_final_sd)</Expression>
</InitProperty>
</Disabled>
-->
<!-- <Disabled>
<InitProperty symbol-ref="cell_area_edge_final">
<Expression>rand_norm(ct1_area_edge_final
,ct1_area_edge_final_sd)</Expression>
</InitProperty>
</Disabled>
-->
</Population>
<Population size="1" type="ct2" name="cell_type_2">
<InitRectangle mode="regular" random-offset="10" number-of-cells="num_cells_ct2">
<Dimensions size="60,20,0" origin="(lattice.x/2)+inhibited_offset_x,(lattice.y/2)+inhibited_offset_y,0"/>
</InitRectangle>
<!-- <Disabled>
<InitCircle mode="random" number-of-cells="25" random_displacement="0.05*lattice.x">
<Dimensions center="lattice.x/2, lattice.y/2,0" radius="10"/>
</InitCircle>
</Disabled>
-->
<InitProperty symbol-ref="dc">
<Expression>rand_uni(0,dt)</Expression>
</InitProperty>
<!-- <Disabled>
<InitProperty symbol-ref="cell_area_final">
<Expression>rand_norm(ct2_area_final,ct2_area_final_sd)</Expression>
</InitProperty>
</Disabled>
-->
<!-- <Disabled>
<InitProperty symbol-ref="cell_area_edge_final">
<Expression>rand_norm(ct2_area_edge_final
,ct2_area_edge_final_sd)</Expression>
</InitProperty>
</Disabled>
-->
</Population>
<!-- <Disabled>
<Population size="1" type="collagen">
<InitRectangle mode="regular" number-of-cells="cell_density*lattice.*lattice.y">
<Dimensions size="lattice.x/2,lattice.y,0" origin="0.0, 0.0, 0.0"/>
</InitRectangle>
</Population>
</Disabled>
-->
<!-- <Disabled>
<Population size="1" type="sisterColony">
<InitCircle mode="regular" number-of-cells="1">
<Dimensions center="100,100,0" radius="1"/>
</InitCircle>
</Population>
</Disabled>
-->
<!-- <Disabled>
<Population size="1" type="ct1" name="wildtype">
<InitCircle mode="random" number-of-cells="75" random_displacement="0.3*lattice.x">
<Dimensions center="50,50,0" radius="20"/>
</InitCircle>
<InitProperty symbol-ref="dc">
<Expression>rand_uni(0,dt)</Expression>
</InitProperty>
<Disabled>
<InitProperty symbol-ref="targetArea">
<Expression>rand_uni(16,32)</Expression>
</InitProperty>
</Disabled>
</Population>
</Disabled>
-->
</CellPopulations>
<Analysis>
<Gnuplotter time-step="1" decorate="false">
<Terminal size="1200,1200,0" name="png"/>
<Plot>
<Cells value="c" max="3" min="0">
<ColorMap>
<Color value="0" color="gray"/>
<Color value="1" color="red"/>
<Color value="2" color="yellow"/>
<Color value="3" color="blue"/>
</ColorMap>
</Cells>
<!-- <Disabled>
<Field symbol-ref="U" surface="true" max="100" min="0.0"/>
</Disabled>
-->
</Plot>
</Gnuplotter>
<!-- <Disabled>
<HistogramLogger normalized="true" maximum="32" time-step="1" minimum="14" number-of-bins="20">
<Column symbol-ref="targetArea" celltype="ct2"/>
<Plot terminal="png" maximum="1" minimum="0.0"/>
</HistogramLogger>
</Disabled>
-->
<!-- <Disabled>
<Logger time-step="1">
<Input>
<Disabled>
<Symbol symbol-ref="cell.id"/>
</Disabled>
<Symbol symbol-ref="cell.center.x"/>
<Symbol symbol-ref="cell.center.y"/>
<Symbol symbol-ref="cell.type"/>
<Disabled>
<Symbol symbol-ref="avgMediaNeighborLength"/>
</Disabled>
<Disabled>
<Symbol symbol-ref="avgLikeNeighborLength"/>
</Disabled>
</Input>
<Output>
<TextOutput file-numbering="time" file-name="cell_positions"/>
</Output>
</Logger>
</Disabled>
-->
<Logger time-step="1">
<Input>
<Symbol symbol-ref="ct1_adhesion"/>
<Symbol symbol-ref="ct1_membrane_str"/>
<Symbol symbol-ref="ct1_area"/>
<Symbol symbol-ref="ct1_area_edge"/>
<Symbol symbol-ref="ct1_membraneElasticity"/>
<Symbol symbol-ref="ct1_membraneElasticity_edge"/>
<Symbol symbol-ref="ct2_adhesion"/>
<Symbol symbol-ref="ct2_membrane_str"/>
<Symbol symbol-ref="ct2_area"/>
<Symbol symbol-ref="ct2_area_edge"/>
<Symbol symbol-ref="ct2_membraneElasticity"/>
<Symbol symbol-ref="ct2_membraneElasticity_edge"/>
</Input>
<Output>
<TextOutput file-numbering="time" file-name="cell_membrane_properties"/>
</Output>
<!-- <Disabled>
<Plots>
<Plot time-step="1">
<Style style="linespoints" grid="true"/>
<Terminal terminal="png"/>
<X-axis>
<Symbol symbol-ref="time"/>
</X-axis>
<Y-axis>
<Symbol symbol-ref="ct1_adhesion"/>
<Symbol symbol-ref="ct2_adhesion"/>
</Y-axis>
</Plot>
</Plots>
</Disabled>
-->
</Logger>
<!-- <Disabled>
<DisplacementTracker celltype="ct1" time-step="1"/>
</Disabled>
-->
<!-- <Disabled>
<DisplacementTracker celltype="ct2" time-step="1"/>
</Disabled>
-->
<ModelGraph include-tags="#untagged" format="dot" reduced="true"/>
</Analysis>
</MorpheusModel>
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