M9147: Liver Regeneration
Model ID: https://identifiers.org/morpheus/M9147 Title: Liver Regeneration from CCl4 Authors: S. Höhme, M. Brulport, A. Bauer, E. Bedawy, W. Schormann, M. Hermes, V. Puppe, R. Gebhardt, S. Zellmer, M. Schwarz, E. Bockamp, T. Timmel, J. G. Hengstler, D. Drasdo Submitters: D. Jahn, L. Brusch Curators: D. Jahn, L. Brusch Date: 12.04.2024 Software: Morpheus (open source). Download from: https://morpheus.gitlab.io Units: [time] = 1 d [space] = 3 µm Reference: This model reproduces a published result, originally obtained with a different simulator: S. Höhme, M. Brulport, A. Bauer, E. Bedawy, W. Schormann, M. Hermes, V. Puppe, R. Gebhardt, S. Zellmer, M. Schwarz, E. Bockamp, T. Timmel, J. G. Hengstler, D. Drasdo: Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. PNAS 107 (23): 10371-10376, 2010. https://doi.org/10.1073/pnas.0909374107
2 Lobule radius in 2D slice (lit.): 284.3 µm Hexagon diameter: 284.3 µm * 2 / node.length = 190 0: tangential 1: radial Factor to scale time from 5 min steps to 1 d time/time_span.day Time in days excluding initialization time (0 ≤ t ≤ time.cell_death). Used for plotting. time.days - hepatocyte.time.death_start Default value for apical adhesive. Value is set per CellType. Common value for all contact energies with hepatocytes involved Common value for //CPM/Interaction/Contact/HomophilicAdhesion/@strength of all possible hepatocyte interactions Diffusion constant converted from cm^2/s to 3 µm^2/5 min: 10e-6 cm^2/s = 10e-6 * (10^4)^2 µm^2/s = 10e-6 * (10^4)^2 / 3^2 (3 µm)^2/s = 10^-6 * 10^8 / 9 * 300 (3 µm)^2/5 min = 3333.3 Global initialization of decay rate. Actual CCl4 depletion occurs only in CellType 'hepatocytes'. cell.type == celltype.medium.id cell.type == celltype.medium.id or cell.type == celltype.CV.id -c.decay*c + (c.target-c)*hepatocyte.lesion.pattern_including_cv Time of one cell cycle in days. Initialization time in days (time of CCl4 administration and full formation of the necrotic lesion). Proliferation window Radius of necrotic lesion before regeneration in NodeLengths. 149 µm = 149/3 NodeLengths (equivalent to 6.4 hepatocytes) Determine area of necrotic lesion by counting the nodes. Convert lesion nodes to lesion area in mm^2. Node area: (3 µm)^2 = 9 µm^2 Conversion: 1 node = 9 * 10^-6 mm^2 Area of necrotic lesion before regeneration (lit.): 0.073 mm^2 hepatocyte.lesion.nodes * node.volume Contains the experimental values for calculating the deviations of the simulation and displaying these values in Gnuplotter. piecewise(0.002, time.regeneration >= -0.25 && time.regeneration <= 0.25, 0.075, time.regeneration >= 0.75 && time.regeneration <= 1.25, 0.061, time.regeneration >= 1.75 && time.regeneration <= 2.25, 0.037, time.regeneration >= 2.75 && time.regeneration <= 3.25, 0.016, time.regeneration >= 3.75 && time.regeneration <= 4.25, 0.003, time.regeneration >= 6.75 && time.regeneration <= 7.25, 0.004, time.regeneration >= 7.75 && time.regeneration <= 8.25, 0.002, time.regeneration >= 15.75 && time.regeneration <= 16.25, 0) Sum up square deviations from experimental values. rint(time.regeneration*10)/10 == 0.0 || rint(time.regeneration*10)/10 == 1.0 || rint(time.regeneration*10)/10 == 2.0 || rint(time.regeneration*10)/10 == 3.0 || rint(time.regeneration*10)/10 == 4.0 || rint(time.regeneration*10)/10 == 7.0 || rint(time.regeneration*10)/10 == 8.0 || rint(time.regeneration*10)/10 == 16.0 hepatocyte.lesion.area_error + (hepatocyte.lesion.area_exp - hepatocyte.lesion.area)^2 1 Set CV color to 5 (medium-blue) to match Höhme et al., SI Movie S9. 1 Set PV color to 4 (light-red) to match Höhme et al., SI Movie S9. Cell diameter (lit.): 23.3 µm CCl4 depletion occurs only in hepatocytes, i.e. CCl4 decay rate is 0 at in all other locations. Assign the value "1" to the MembraneProperty on apical sides (± 45°; ± π/4) of the hepatocytes. Needed for homophilic adhesion. - Use cos() version for apical sides perpendicular to sinusoids (tangential). - Use sin() version for apical sides parallel to sinusoids (radial). apical.polarization == 0 ? (abs(cos(membrane.phi - hepatocyte.sinusoid_mean.phi)) <= sin(pi/4) ? 1 : 0) : (abs(sin(membrane.phi - hepatocyte.sinusoid_mean.phi)) <= sin(pi/4) ? 1 : 0) Assign death times to all hepatocytes within lesion radius. if(time.days >= hepatocyte.time.death_start && time.days < hepatocyte.time.death_end && hepatocyte.sinusoid_mean.abs <= hepatocyte.lesion.radius && hepatocyte.time.death == -1, rand_uni(time.days, hepatocyte.time.death_end), hepatocyte.time.death) hepatocyte.time.death > -1 && time.days >= hepatocyte.time.death Determination of the proliferating cell layers if(hepatocyte.location.has_contact_to_lesion==1,1,hepatocyte.layer.neighbor+1) Definition of the cell division probability of BrdU-positive hepatocytes depending on the the layer number. if(time.regeneration >= 2.9 - hepatocyte.time_span.proliferation/2 && time.regeneration < 2.9 + hepatocyte.time_span.proliferation/2, if(hepatocyte.layer.self == 1, 0.3, if(hepatocyte.layer.self == 2, 0.25, if(hepatocyte.layer.self == 3, 0.2, if(hepatocyte.layer.self == 4, 0.2, 0.1)))), 0) time.days > hepatocyte.time.birth + hepatocyte.time_span.cell_cycle && rand_uni(0,1) < (hepatocyte.proliferation_scaling*hepatocyte.proliferation_p / (time_span.day/mcs_duration)) time.days Set hepatocyte colors to match Höhme et al., SI Movie S9. Color 0 (light-salmon) : Hepatocyte standard color Color 1 (tan1) : Pericentral hepatocytes Color 2 (beige) : Necrotic hepatocytes Color 3 (light-coral) : Daughter hepatocytes piecewise(1, hepatocyte.sinusoid_mean.abs <= (41.2 + 2.0*23.3) / node.length, 2, hepatocyte.time.death > -1, 3, time.days >= hepatocyte.time.birth && time.days < hepatocyte.time.birth + 0.9, 0) 2 3 Reproduction of SI Movie S9 from Höhme et al. Color 0 (light-salmon) : Hepatocyte standard color Color 1 (beige) : Necrotic hepatocytes Color 2 (light-coral) : Daughter hepatocytes Color 3 (tan1) : Pericentral hepatocytes Color 4 (light-red) : CV Color 5 (medium-blue) : PVs