Human iPSC ROCK1-KD : Wildtype Colony Patterning

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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 by Libby et al. to in vitro cell culture experiments of hiPSC colony growth. Here, the ROCK1-KD (ROCK1 is a protein kinase) in some of the cells indirectly modulates the actomyosin cytoskeletal tension. The corresponding parameter changes break the symmetry and lead to patterning into layers of perturbed cells surrounded by wt cells.
  • In this CPM-based model, the primary determinant of global patterning is the strength of cortical tension. 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, random intial positions, 100 total cells densely clustered, wildtype (shown grey) and ROCK1-KD (shown red) cells were mixed in a 1:3 ratio.
  • 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.
  • Note that the published model file has set generic values for some of the parameters while the authors' script MorpheusSetup.py defines the parameter set as used for the results, i.e. num_cells_ct2=25 (wt cells, hence num_cells_ct1=75 ROCK1-KD cells), ct1_perturbation_time=0 (p.487 bottom right: “KD of gene expression was induced upon mixing”), ct1_adhesion_weak=-85, ct1_membrane_str_final=1.1. These parameter values were fixed in the new model file provided below together with added data loggers. These parameter settings were generated and placed in the base model AdhesionDriven_CellModel_v5.7.2.latest.xml by calling the setup script like this: python2 MorpheusSetup.py –simulation_time 120 wildtype -144 ROCK1-20 0 75 0
  • The new model file provided below has been updated (solver naming, added ctall_medium_adhesion_init = 0 in Global to ease initialization of CellTypes, 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 ROCK1-KD : WT mixed cell culture simulation as published in Video S6 of Libby et al. The spatio-temporal pattern matches the experiment (ROCK1-KD cells are mCherry-labelled and shown in red, WT in grey) as published in Video S5 of Libby et al. The following figure shows a snapshot of the simulation state at $96\ \mathrm h$ and qualitatively reproduces Fig.2I.

Model results reproduced with this Morpheus model.
Model results reproduced with this Morpheus model.

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

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<?xml version='1.0'?>
<MorpheusModel version="4">
    <Description>
        <Title>Libby2019</Title>
        <Details>Full title:        Human iPSC ROCK1-KD : Wildtype Colony Patterning.
Date: 	03.06.2021
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/M7673
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. (cf. Video S6 at https://www.sciencedirect.com/science/article/pii/S2405471219303849?#mmc8)
</Details>
    </Description>
    <Global>
        <Variable symbol="ct1_adhesion" value="-100"/>
        <Variable symbol="ct2_adhesion" value="-100"/>
        <Variable symbol="ct1_ct2" value="max(ct1_adhesion,ct2_adhesion)"/>
        <Constant symbol="ctall_medium_adhesion_init" value="0"/>
        <Variable symbol="ctall_medium_adhesion" value="ctall_medium_adhesion_init"/>
        <Variable name="time_of_knockout_initiation_ct1_adhesion" symbol="ct1_perturbation_time" value="-144"/>
        <Constant symbol="adhesion_init_ct1" value="-100"/>
        <Variable symbol="ct1_adhesion_weak" value="-100"/>
        <Variable symbol="ct1_membraneElasticity_init" value="1.12"/>
        <Variable symbol="ct1_membraneElasticity" value="1.12"/>
        <Variable symbol="ct1_membraneElasticity_final" value="1.12"/>
        <Variable symbol="ct1_membraneElasticity_edge_init" value="1.32"/>
        <Variable symbol="ct1_membraneElasticity_edge" value="1.32"/>
        <Variable symbol="ct1_membraneElasticity_final_edge" value="1.32"/>
        <Variable symbol="ct1_k_half_hours" value="48.28"/>
        <Variable name="" symbol="ct1_hill_n" value="5.0"/>
        <Variable symbol="ct1_area_init" value="137"/>
        <Variable name="" symbol="ct1_area" value="137"/>
        <Variable name="" symbol="ct1_area_final" value="137"/>
        <Variable symbol="ct1_area_final_sd" value="34.03"/>
        <Variable symbol="ct1_area_edge_init" value="177"/>
        <Variable name="" symbol="ct1_area_edge" value="177"/>
        <Variable name="" symbol="ct1_area_edge_final" value="177"/>
        <Variable symbol="ct1_area_edge_final_sd" value="49.66"/>
        <Variable symbol="ct1_generation_time_init" value="20"/>
        <Variable symbol="ct1_generation_time_final" value="20"/>
        <Variable symbol="ct1_generation_time" value="20"/>
        <Variable symbol="ct1_membrane_str_init" value="0.5"/>
        <Variable symbol="ct1_membrane_str_final" value="0.5"/>
        <Variable symbol="ct1_membrane_str" value="0.5"/>
        <Variable symbol="ct1_persistent_motion_str_init" value="9"/>
        <Variable symbol="ct1_persistent_motion_str_final" value="9"/>
        <Variable symbol="ct1_persistent_motion" value="9"/>
        <Variable name="time_of_knockout_initiation_ct2_adhesion" symbol="ct2_perturbation_time" value="0"/>
        <Constant symbol="adhesion_init_ct2" value="-100"/>
        <Variable symbol="ct2_adhesion_weak" value="-85"/>
        <Variable symbol="ct2_membraneElasticity_init" value="1.12"/>
        <Variable symbol="ct2_membraneElasticity" value="1.12"/>
        <Variable symbol="ct2_membraneElasticity_final" value="1.17"/>
        <Variable symbol="ct2_membraneElasticity_edge_init" value="1.32"/>
        <Variable symbol="ct2_membraneElasticity_edge" value="1.32"/>
        <Variable symbol="ct2_membraneElasticity_final_edge" value="1.41"/>
        <Variable symbol="ct2_k_half_hours" value="46.78"/>
        <Variable symbol="ct2_hill_n" value="5.0"/>
        <Variable symbol="ct2_area_init" value="137"/>
        <Variable symbol="ct2_area" value="137"/>
        <Variable symbol="ct2_area_final_sd" value="53.54"/>
        <Variable symbol="ct2_area_final" value="170"/>
        <Variable symbol="ct2_area_edge_init" value="177"/>
        <Variable symbol="ct2_area_edge" value="177"/>
        <Variable symbol="ct2_area_edge_final" value="228"/>
        <Variable symbol="ct2_area_edge_final_sd" value="60.06"/>
        <Variable symbol="ct2_generation_time_init" value="20"/>
        <Variable symbol="ct2_generation_time_final" value="20"/>
        <Variable symbol="ct2_generation_time" value="20"/>
        <Variable symbol="ct2_membrane_str_init" value="0.5"/>
        <Variable symbol="ct2_membrane_str_final" value="1.1"/>
        <Variable symbol="ct2_membrane_str" value="0.5"/>
        <Variable symbol="ct2_persistent_motion_str_init" value="9"/>
        <Variable symbol="ct2_persistent_motion_str_final" value="9"/>
        <Variable symbol="ct2_persistent_motion" value="9"/>
        <System solver="Euler [fixed, O(1)]" name="ct1_mechanics_updater" time-step="0.1">
            <Rule symbol-ref="ct1_adhesion">
                <Expression>if(time &lt; burn_in_time, adhesion_init_ct1,
  if(time > ct1_perturbation_time
  and ct1_adhesion >= adhesion_init_ct1
  and ct1_adhesion &lt;= 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 &lt;= ct1_perturbation_time,adhesion_init_ct1,ct1_adhesion_weak)
))</Expression>
            </Rule>
            <Rule symbol-ref="ct1_membraneElasticity">
                <Expression>if(time &lt; burn_in_time,ct1_membraneElasticity_init,
  if(time > ct1_perturbation_time 
  and ct1_membraneElasticity >= ct1_membraneElasticity_init
  and ct1_membraneElasticity &lt;= 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 &lt;= ct1_perturbation_time,ct1_membraneElasticity_init,ct1_membraneElasticity_final)
))</Expression>
            </Rule>
            <Rule symbol-ref="ct1_membraneElasticity_edge">
                <Expression>if(time &lt; burn_in_time,ct1_membraneElasticity_edge_init,
  if(time > ct1_perturbation_time 
    and ct1_membraneElasticity_edge >= ct1_membraneElasticity_edge_init
    and ct1_membraneElasticity_edge &lt;= 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 &lt;= 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 &lt; ct1_area_final) 
     and ct1_area &lt; 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 &lt; burn_in_time,ct1_area_edge_init,
  if((ct1_area_edge_init &lt; ct1_area_edge_final) 
     and ct1_area_edge &lt; 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 &lt; 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 &lt;= ct1_perturbation_time,ct1_generation_time_init,ct1_generation_time_final)
))
</Expression>
            </Rule>
            <Rule symbol-ref="ct1_membrane_str">
                <Expression>if(time &lt; burn_in_time, ct1_membrane_str_init,
  if(time > ct1_perturbation_time
  and ct1_membrane_str >= ct1_membrane_str_init
  and ct1_membrane_str &lt;= 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 &lt;= ct1_perturbation_time,ct1_membrane_str_init,ct1_membrane_str_final)
))</Expression>
            </Rule>
        </System>
        <System solver="Euler [fixed, O(1)]" name="ct2_mechanics_updater" time-step="0.1">
            <Rule symbol-ref="ct2_adhesion">
                <Expression>if(time &lt; burn_in_time,adhesion_init_ct2,
  if(time > ct2_perturbation_time 
  and ct2_adhesion >= adhesion_init_ct2
  and ct2_adhesion &lt;= 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 &lt;= ct2_perturbation_time,adhesion_init_ct2,ct2_adhesion_weak)
))</Expression>
            </Rule>
            <Rule symbol-ref="ct2_membraneElasticity">
                <Expression>if(time &lt; burn_in_time,ct2_membraneElasticity_init,
  if(time > ct2_perturbation_time 
  and ct2_membraneElasticity >= ct2_membraneElasticity_init
  and ct2_membraneElasticity &lt;= 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 &lt;= ct2_perturbation_time,ct2_membraneElasticity_init,ct2_membraneElasticity_final)
))</Expression>
            </Rule>
            <Rule symbol-ref="ct2_membraneElasticity_edge">
                <Expression>if(time &lt; burn_in_time,ct2_membraneElasticity_edge_init,
  if(time > ct2_perturbation_time 
  and ct2_membraneElasticity_edge >= ct2_membraneElasticity_edge_init
  and ct2_membraneElasticity_edge &lt;= 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 &lt;= ct2_perturbation_time,ct2_membraneElasticity_edge_init,ct2_membraneElasticity_final_edge)
))</Expression>
            </Rule>
            <Rule symbol-ref="ct2_area">
                <Expression>if(time &lt; burn_in_time,ct2_area_init,
  if( (ct2_area_init &lt; ct2_area_final)
    and ct2_area &lt; 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 &lt; burn_in_time,ct2_area_edge_init,
  if( (ct2_area_edge_init &lt; ct2_area_edge_final)
     and ct2_area_edge &lt; 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 &lt; 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 &lt;= ct2_perturbation_time,ct2_generation_time_init,ct2_generation_time_final)
))
</Expression>
            </Rule>
            <Rule symbol-ref="ct2_membrane_str">
                <Expression>if(time &lt; burn_in_time, ct2_membrane_str_init,
  if(time > ct2_perturbation_time
  and ct2_membrane_str >= ct2_membrane_str_init
  and ct2_membrane_str &lt;= 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 &lt;= ct2_perturbation_time,ct2_membrane_str_init,ct2_membrane_str_final)
))</Expression>
            </Rule>
        </System>
        <System solver="Euler [fixed, O(1)]" name="adhesion_ct1_ct2" time-step="0.1">
            <Rule symbol-ref="ct1_ct2">
                <Expression>max(ct1_adhesion,ct2_adhesion)</Expression>
            </Rule>
        </System>
        <Constant symbol="wt_offset_x" value="0"/>
        <Constant symbol="wt_offset_y" value="0"/>
        <Constant symbol="inhibited_offset_x" value="0"/>
        <Constant symbol="inhibited_offset_y" value="0"/>
        <Field name="chemoattractant" symbol="U" value="0">
            <Diffusion rate="0"/>
        </Field>
        <!--    <Disabled>
        <System solver="Euler [fixed, O(1)]" time-step="1">
            <DiffEqn symbol-ref="U">
                <Expression>p-degp*U</Expression>
            </DiffEqn>
        </System>
    </Disabled>
-->
        <!--    <Disabled>
        <Constant symbol="cell_density" value="0.003"/>
    </Disabled>
-->
        <!--    <Disabled>
        <Field symbol="protrusionMemory" value="0">
            <Diffusion rate="0.0"/>
        </Field>
    </Disabled>
-->
        <Variable symbol="num_cells_ct2" value="75"/>
        <Variable symbol="num_cells_ct1" value="100-num_cells_ct2"/>
        <Variable name="percent_membrane_bordeing_media" symbol="avgMediaNeighborLength" value="1"/>
        <Variable symbol="burn_in_time" value="5"/>
        <Variable name="Boundary length of CT1 with other cell types" symbol="boundary" value="0.0"/>
    </Global>
    <Space>
        <Lattice class="square">
            <Size symbol="lattice" value="1200,1200,0"/>
            <BoundaryConditions>
                <Condition type="constant" boundary="x"/>
                <Condition type="constant" boundary="y"/>
            </BoundaryConditions>
            <Neighborhood>
                <Order>4</Order>
            </Neighborhood>
        </Lattice>
        <SpaceSymbol symbol="space"/>
    </Space>
    <Time>
        <StartTime value="0"/>
        <StopTime symbol="hours" value="120"/>
        <TimeSymbol symbol="time"/>
        <RandomSeed value="0"/>
    </Time>
    <CellTypes>
        <CellType class="biological" name="ct1">
            <Property name="divisions" symbol="d" value="0"/>
            <Property name="color" symbol="c" value="0"/>
            <Property name="generationTime" symbol="dt" value="ct1_generation_time"/>
            <Property name="division_time_counter" symbol="dc" value="0.0"/>
            <Property name="cell (for counting)" symbol="cell" value="1.0"/>
            <Property symbol="cadherin" value="ct1_adhesion"/>
            <Property symbol="ct1_ct2_adhesion" value="ct1_ct2"/>
            <!--    <Disabled>
        <Property name="percentVolume2DaughterCell" symbol="percentDaughterVolume" value="0.5"/>
    </Disabled>
-->
            <!--    <Disabled>
        <Constant symbol="maxTargetArea" value="32.0"/>
    </Disabled>
-->
            <!--    <Disabled>
        <Property symbol="cellVolumeIncrement" value="0.5*maxTargetArea/dt"/>
    </Disabled>
-->
            <Property symbol="targetArea" value="ct1_area"/>
            <Property symbol="targetSurface" value="ct1_membraneElasticity"/>
            <VolumeConstraint strength="1.0" target="targetArea"/>
            <SurfaceConstraint strength="ct1_membrane_str" mode="aspherity" target="targetSurface"/>
            <PropertyVector name="direction_vector" symbol="dv" value="0.0, 0.0, 0.0"/>
            <PersistentMotion decay-time="0.003" strength="9" protrusion="true"/>
            <!--    <Disabled>
        <Event name="partitionCell" trigger="when true">
            <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 solver="Euler [fixed, O(1)]" name="cell_state_updater" time-step="1">
                <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 symbol="displacement" value=""/>
    </Disabled>
-->
            <!--    <Disabled>
        <MotilityReporter time-step="1">
            <Displacement symbol-ref="displacement"/>
        </MotilityReporter>
    </Disabled>
-->
            <Property symbol="p" value="10"/>
            <Chemotaxis field="U" strength="3" contact-inhibition="true" retraction="true"/>
            <Constant symbol="degp" value="0.9"/>
            <!--    <Disabled>
        <Protrusion field="protrusionMemory" strength="1" maximum="10"/>
    </Disabled>
-->
            <Property symbol="isEdgeCell" value="0"/>
            <NeighborhoodReporter>
                <Input scaling="cell" value="cell.type == celltype.medium.id"/>
                <Output symbol-ref="isEdgeCell" mapping="sum"/>
            </NeighborhoodReporter>
            <Property symbol="ctall_medium_adhesion" value="ctall_medium_adhesion_init"/>
            <Property symbol="cell_area_final" value="0"/>
            <Property symbol="cell_area_edge_final" value="0"/>
            <NeighborhoodReporter time-step="1.0">
                <Input scaling="length" value="cell.type == celltype.ct2.id"/>
                <Output symbol-ref="boundary" mapping="sum"/>
            </NeighborhoodReporter>
        </CellType>
        <CellType class="biological" name="ct2">
            <Property name="divisions" symbol="d" value="0"/>
            <Property name="color" symbol="c" value="1"/>
            <Property name="cell (for counting)" symbol="cell" value="1.0"/>
            <Property name="generationTime" symbol="dt" value="ct2_generation_time"/>
            <Property name="division_time_counter" symbol="dc" value="0.0"/>
            <Property name="global_cadherin_inhibitedpop" symbol="cadherin" value="ct2_adhesion"/>
            <Property symbol="ct1_ct2_adhesion" value="ct1_ct2"/>
            <Property symbol="ctall_medium_adhesion" value="ctall_medium_adhesion_init"/>
            <Property symbol="avgLikeNeighborCount" value="0"/>
            <Property symbol="avgLikeNeighborLength" value="0"/>
            <Property symbol="targetArea" value="ct2_area"/>
            <Property symbol="targetSurface" value="ct2_membraneElasticity"/>
            <VolumeConstraint strength="1" target="targetArea"/>
            <SurfaceConstraint strength="ct2_membrane_str" mode="aspherity" target="targetSurface"/>
            <PropertyVector name="direction_vector" symbol="dv" value="0.0, 0.0, 0.0"/>
            <PersistentMotion decay-time="0.003" strength="9" protrusion="true"/>
            <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 solver="Euler [fixed, O(1)]" name="cell_state_updater" time-step="1">
                <Rule symbol-ref="dc">
                    <Expression>dc+1</Expression>
                </Rule>
                <!--    <Disabled>
        <Rule symbol-ref="c">
            <Expression>if(isEdgeCell > 0,2,1)</Expression>
        </Rule>
    </Disabled>
-->
                <Rule name="CellGrowth" symbol-ref="targetArea">
                    <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 name="peripheral_cell_migration" symbol-ref="ctall_medium_adhesion">
            <Expression>if(avgMediaNeighborLength > 0.35,max(cadherin,ct1_ct2_adhesion)/2,0)</Expression>
        </Rule>
    </Disabled>
-->
            </System>
            <!--    <Disabled>
        <PropertyVector symbol="displacement" value=""/>
    </Disabled>
-->
            <!--    <Disabled>
        <MotilityReporter time-step="1">
            <Displacement symbol-ref="displacement"/>
        </MotilityReporter>
    </Disabled>
-->
            <Property symbol="p" value="10"/>
            <Constant symbol="degp" value="0.9"/>
            <Chemotaxis field="U" strength="3" contact-inhibition="true" retraction="true"/>
            <!--    <Disabled>
        <Protrusion field="protrusionMemory" strength="1" maximum="10"/>
    </Disabled>
-->
            <Property symbol="isEdgeCell" value="0"/>
            <NeighborhoodReporter>
                <Input scaling="cell" value="cell.type == celltype.medium.id"/>
                <Output symbol-ref="isEdgeCell" mapping="sum"/>
            </NeighborhoodReporter>
            <Property symbol="cell_area_final" value="0"/>
            <Property symbol="cell_area_edge_final" value="0"/>
        </CellType>
        <!--    <Disabled>
        <CellType class="biological" name="collagen">
            <Property name="divisions" symbol="d" value="0"/>
            <Property name="color" symbol="c" value="2"/>
            <Property name="cell (for counting)" symbol="cell" value="1.0"/>
            <Disabled>
                <Property name="generationTime" symbol="dt" value="20"/>
            </Disabled>
            <Property name="division_time_counter" symbol="dc" value="0.0"/>
            <Property symbol="targetArea" value="10"/>
            <Property name="global_cadherin_inhibitedpop" symbol="cadherin" value="2"/>
            <Disabled>
                <Property symbol="avgLikeNeighborCount" value="0"/>
            </Disabled>
            <Disabled>
                <Property symbol="avgLikeNeighborLength" value="0"/>
            </Disabled>
            <VolumeConstraint strength="1" target="targetArea"/>
            <PropertyVector name="direction_vector" symbol="dv" value="0.0, 0.0, 0.0"/>
            <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 symbol="ct1_ct2_adhesion" value="2"/>
            <Property symbol="p" value="0.10"/>
            <Disabled>
                <Chemotaxis field="U" strength="c" contact-inhibition="false" retraction="true"/>
            </Disabled>
            <FreezeMotion>
                <Condition>time >=5</Condition>
            </FreezeMotion>
        </CellType>
    </Disabled>
-->
        <CellType class="medium" name="medium">
            <Property symbol="cadherin" value="ctall_medium_adhesion"/>
            <Property symbol="avgLikeNeighborCount" value="0"/>
            <Property symbol="avgLikeNeighborLength" value="0"/>
            <Property symbol="p" value="0"/>
            <!--    <Disabled>
        <Property symbol="dc" value="0"/>
    </Disabled>
-->
            <Constant symbol="degp" value="0.0"/>
        </CellType>
        <!--    <Disabled>
        <CellType class="biological" name="sisterColony">
            <Property name="divisions" symbol="d" value="0"/>
            <Property name="color" symbol="c" value="3"/>
            <Property name="cell (for counting)" symbol="cell" value="1.0"/>
            <Disabled>
                <Property name="generationTime" symbol="dt" value="20"/>
            </Disabled>
            <Property name="division_time_counter" symbol="dc" value="0.0"/>
            <Property symbol="targetArea" value="500"/>
            <Property name="global_cadherin_inhibitedpop" symbol="cadherin" value="2"/>
            <Disabled>
                <Property symbol="avgLikeNeighborCount" value="0"/>
            </Disabled>
            <Disabled>
                <Property symbol="avgLikeNeighborLength" value="0"/>
            </Disabled>
            <VolumeConstraint strength="1" target="targetArea"/>
            <PropertyVector name="direction_vector" symbol="dv" value="0.0, 0.0, 0.0"/>
            <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 symbol="ct1_ct2_adhesion" value="2"/>
            <Property symbol="p" value="500"/>
            <Disabled>
                <Chemotaxis field="U" strength="c" contact-inhibition="false" retraction="true"/>
            </Disabled>
            <Disabled>
                <FreezeMotion>
                    <Condition>time >=5</Condition>
                </FreezeMotion>
            </Disabled>
            <SurfaceConstraint strength="1" mode="aspherity" target="0.5"/>
        </CellType>
    </Disabled>
-->
    </CellTypes>
    <CPM>
        <Interaction default="0">
            <Contact type1="ct1" type2="medium" value="0">
                <HomophilicAdhesion strength="1" adhesive="ctall_medium_adhesion"/>
            </Contact>
            <Contact type1="ct2" type2="medium" value="0">
                <HomophilicAdhesion strength="1" adhesive="ctall_medium_adhesion"/>
            </Contact>
            <Contact type1="ct1" type2="ct1" value="0">
                <HomophilicAdhesion strength="1" adhesive="cadherin"/>
            </Contact>
            <Contact type1="ct1" type2="ct2" value="0">
                <HomophilicAdhesion strength="1" adhesive="ct1_ct2"/>
            </Contact>
            <Contact type1="ct2" type2="ct2" value="0">
                <HomophilicAdhesion strength="1" adhesive="cadherin"/>
            </Contact>
        </Interaction>
        <MonteCarloSampler stepper="edgelist">
            <MCSDuration value="0.03"/>
            <Neighborhood>
                <Order>4</Order>
            </Neighborhood>
            <MetropolisKinetics temperature="10" yield="0.1"/>
        </MonteCarloSampler>
        <ShapeSurface scaling="norm">
            <Neighborhood>
                <Order>1</Order>
            </Neighborhood>
        </ShapeSurface>
    </CPM>
    <CellPopulations>
        <Population name="cell_type_1" type="ct1" size="1">
            <!--    <Disabled>
        <InitCircle mode="random" random_displacement="0.3*lattice.x" number-of-cells="75">
            <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 random-offset="10" mode="regular" number-of-cells="num_cells_ct1">
                <Dimensions origin="(lattice.x/2)+wt_offset_x,(lattice.y/2)+wt_offset_y,0" size="60,20,0"/>
            </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 name="cell_type_2" type="ct2" size="1">
            <InitRectangle random-offset="10" mode="regular" number-of-cells="num_cells_ct2">
                <Dimensions origin="(lattice.x/2)+inhibited_offset_x,(lattice.y/2)+inhibited_offset_y,0" size="60,20,0"/>
            </InitRectangle>
            <!--    <Disabled>
        <InitCircle mode="random" random_displacement="0.05*lattice.x" number-of-cells="25">
            <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 type="collagen" size="1">
            <InitRectangle mode="regular" number-of-cells="cell_density*lattice.*lattice.y">
                <Dimensions origin="0.0, 0.0, 0.0" size="lattice.x/2,lattice.y,0"/>
            </InitRectangle>
        </Population>
    </Disabled>
-->
        <!--    <Disabled>
        <Population type="sisterColony" size="1">
            <InitCircle mode="regular" number-of-cells="1">
                <Dimensions center="100,100,0" radius="1"/>
            </InitCircle>
        </Population>
    </Disabled>
-->
        <!--    <Disabled>
        <Population type="ct1" name="wildtype" size="1">
            <InitCircle mode="random" random_displacement="0.3*lattice.x" number-of-cells="75">
                <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 decorate="false" time-step="1">
            <Terminal name="png" size="1200,1200,0"/>
            <Plot>
                <Cells max="3" value="c" min="0">
                    <ColorMap>
                        <Color color="dark-gray" value="0"/>
                        <Color color="red" value="1"/>
                        <Color color="yellow" value="2"/>
                        <Color color="blue" value="3"/>
                    </ColorMap>
                </Cells>
                <!--    <Disabled>
        <Field max="100" surface="true" symbol-ref="U" min="0.0"/>
    </Disabled>
-->
            </Plot>
        </Gnuplotter>
        <!--    <Disabled>
        <HistogramLogger minimum="14" time-step="1" normalized="true" maximum="32" number-of-bins="20">
            <Column celltype="ct2" symbol-ref="targetArea"/>
            <Plot minimum="0.0" terminal="png" maximum="1"/>
        </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 grid="true" style="linespoints"/>
                <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 reduced="true" format="dot" include-tags="#untagged"/>
        <Logger time-step="1">
            <Input/>
            <Output>
                <TextOutput/>
            </Output>
            <Plots>
                <Plot time-step="-1">
                    <Style style="points"/>
                    <Terminal terminal="png"/>
                    <X-axis>
                        <Symbol symbol-ref="time"/>
                    </X-axis>
                    <Y-axis>
                        <Symbol symbol-ref="celltype.ct1.size"/>
                        <Symbol symbol-ref="celltype.ct2.size"/>
                    </Y-axis>
                </Plot>
            </Plots>
        </Logger>
        <Logger time-step="1">
            <Input>
                <Symbol symbol-ref="boundary"/>
            </Input>
            <Output>
                <TextOutput/>
            </Output>
            <Plots>
                <Plot time-step="-1">
                    <Style style="linespoints"/>
                    <Terminal terminal="png"/>
                    <X-axis>
                        <Symbol symbol-ref="time"/>
                    </X-axis>
                    <Y-axis>
                        <Symbol symbol-ref="boundary"/>
                    </Y-axis>
                </Plot>
            </Plots>
        </Logger>
    </Analysis>
</MorpheusModel>

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