{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:51:33Z","timestamp":1760147493435,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Entropy"],"abstract":"<jats:p>Communication between cells enables the coordination that drives structural and functional complexity in biological systems. Both single and multicellular organisms have evolved diverse communication systems for a range of purposes, including synchronization of behavior, division of labor, and spatial organization. Synthetic systems are also increasingly being engineered to utilize cell\u2013cell communication. While research has elucidated the form and function of cell\u2013cell communication in many biological systems, our knowledge is still limited by the confounding effects of other biological phenomena at play and the bias of the evolutionary background. In this work, our goal is to push forward the context-free understanding of what impact cell\u2013cell communication can have on cellular and population behavior to more fully understand the extent to which cell\u2013cell communication systems can be utilized, modified, and engineered. We use an in silico model of 3D multiscale cellular populations, with dynamic intracellular networks interacting via diffusible signals. We focus on two key communication parameters: the effective interaction distance at which cells are able to interact and the receptor activation threshold. We found that cell\u2013cell communication can be divided into six different forms along the parameter axes, three asocial and three social. We also show that cellular behavior, tissue composition, and tissue diversity are all highly sensitive to both the general form and specific parameters of communication even when the cellular network has not been biased towards that behavior.<\/jats:p>","DOI":"10.3390\/e25020319","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T02:33:27Z","timestamp":1675996407000},"page":"319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterizing the Impact of Communication on Cellular and Collective Behavior Using a Three-Dimensional Multiscale Cellular Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1069-1792","authenticated-orcid":false,"given":"Moriah","family":"Echlin","sequence":"first","affiliation":[{"name":"Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, FI-33014 Tampere, Finland"},{"name":"Institute for Systems Biology, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boris","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4410-8780","authenticated-orcid":false,"given":"Ilya","family":"Shmulevich","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nature15709","article-title":"Ion Channels Enable Electrical Communication in Bacterial Communities","volume":"527","author":"Prindle","year":"2015","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.cels.2018.06.005","article-title":"Signal Percolation within a Bacterial Community","volume":"7","author":"Larkin","year":"2018","journal-title":"Cell Syst."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a012427","DOI":"10.1101\/cshperspect.a012427","article-title":"Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control","volume":"2","author":"Rutherford","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1098\/rstb.2000.0607","article-title":"Quorum Sensing and the Population-dependent Control of Virulence","volume":"355","author":"Williams","year":"2000","journal-title":"Philos. Trans. R. Soc. Lond. Ser. Biol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12855","DOI":"10.1038\/s41598-017-13183-9","article-title":"Cell-cell Communication Enhances Bacterial Chemotaxis Toward External Attractants","volume":"7","author":"Long","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6459","DOI":"10.1073\/pnas.0810878106","article-title":"Complexity in Bacterial Cell\u2013cell Communication: Quorum Signal Integration and Subpopulation Signaling in the Bacillus subtilis Phosphorelay","volume":"106","author":"Bischofs","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1101\/gad.1813709","article-title":"Paracrine Signaling in a Bacterium","volume":"23","author":"Vlamakis","year":"2009","journal-title":"Genes Dev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"van Gestel, J., Vlamakis, H., and Kolter, R. (2015). From Cell Differentiation to Cell Collectives: Bacillus subtilis Uses Division of Labor to Migrate. PLoS Biol., 13.","DOI":"10.1371\/journal.pbio.1002141"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1126\/science.282.5390.935","article-title":"Heterocyst Pattern Formation Controlled by a Diffusible Peptide","volume":"282","author":"Yoon","year":"1998","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1046\/j.1365-2958.2001.02437.x","article-title":"The Role of HetN in Maintenance of the Heterocyst Pattern in Anabaena sp. PCC 7120","volume":"40","author":"Callahan","year":"2001","journal-title":"Mol. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1101\/gad.1645008","article-title":"Control of Cell Fate by the Formation of an Architecturally Complex Bacterial Community","volume":"22","author":"Vlamakis","year":"2008","journal-title":"Genes Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1103\/PhysRevLett.75.2899","article-title":"Cooperative Formation of Chiral Patterns during Growth of Bacterial Colonies","volume":"75","author":"Cohen","year":"1995","journal-title":"Phys. Rev. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ghannoum, M., Parsek, M., Whiteley, M., and Mukherjee, P.K. (2015). Microbial Biofilms, ASM Press. [2nd ed.].","DOI":"10.1128\/9781555817466"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/ede.12013","article-title":"The Origins of Multicellular Organisms","volume":"15","author":"Niklas","year":"2013","journal-title":"Evol. Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev.genet.42.110807.091513","article-title":"The Origins of Multicellularity and the Early History of the Genetic Toolkit For Animal Development","volume":"42","author":"Rokas","year":"2008","journal-title":"Annu. Rev. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3389\/fpls.2015.00324","article-title":"Cell Walls as a Stage for Intercellular Communication Regulating Shoot Meristem Development","volume":"6","author":"Tameshige","year":"2015","journal-title":"Front. Plant Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1242\/dev.083428","article-title":"Intercellular Calcium Signaling in a Gap Junction-coupled Cell Network Establishes Assymmetric Neuronal Fates in C. elegans","volume":"139","author":"Schumacher","year":"2012","journal-title":"Development"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.devcel.2006.02.019","article-title":"Chemokine Signaling Mediates Self-Organizing Tissue Migration in the Zebrafish Lateral Line","volume":"10","author":"Haas","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E679","DOI":"10.1073\/pnas.1516503113","article-title":"Cell\u2013cell Communication Enhances the Capacity of Cell Ensembles to Sense Shallow Gradients During Morphogenesis","volume":"113","author":"Ellison","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1242\/dev.128.11.2075","article-title":"Role of FGFs in the Control of Programmed Cell Death During Limb Development","volume":"128","author":"Montero","year":"2001","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0092-8674(02)00871-1","article-title":"The Drosophila Hox Gene Deformed Sculpts Head Morphology via Direct Regulation of the Apoptosis Activator reaper","volume":"110","author":"Lohmann","year":"2002","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.cell.2014.07.033","article-title":"Paradoxical Signaling by a Secreted Molecule Leads to Homeostasis of Cell Levels","volume":"158","author":"Hart","year":"2014","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.cell.2018.01.015","article-title":"Circuit Design Features of a Stable Two-Cell System","volume":"172","author":"Zhou","year":"2018","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/S0002-9394(03)00085-0","article-title":"Corneal Cells: Chatty in Development, Homeostasis, Wound Healing, and Disease","volume":"136","author":"Wilson","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.1007\/s00018-010-0479-3","article-title":"Cellular Communications in Bone Homeostasis and Repair","volume":"67","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature07039","article-title":"Wound Repair and Regeneration","volume":"453","author":"Gurtner","year":"2008","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0306-4492(78)90083-7","article-title":"The Mode of Action of Acetylcholine and 5-hydroxytryptamine at the Neuromuscular Junctions in a Molluscan Muscle (Radular Protractor)","volume":"60","author":"Kobayashi","year":"1978","journal-title":"Comp. Biochem. Physiol. Part C Comp. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1242\/jeb.038315","article-title":"Understanding the Vertebrate Immune System: Insights from the Reptilian Perspective","volume":"213","author":"Zimmerman","year":"2010","journal-title":"J. Exp. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Shklarsh, A., Ariel, G., Schneidman, E., and Ben-Jacob, E. (2011). Smart Swarms of Bacteria-Inspired Agents with Performance Adaptable Interactions. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002177"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/msb.2013.55","article-title":"Temporal Control of Self-organized Pattern Formation Without Morphogen Gradients in Bacteria","volume":"9","author":"Payne","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1126\/science.aat0271","article-title":"Programming Self-organizing Multicellular Structures with Synthetic Cell-cell Signaling","volume":"361","author":"Toda","year":"2018","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature09565","article-title":"Robust Multicellular Computing Using Genetically Encoded NOR Gates and Chemical \u2018Wires\u2019","volume":"469","author":"Tamsir","year":"2010","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1007\/s00253-011-3762-9","article-title":"Developing Symbiotic Consortia for Lignocellulosic Biofuel Production","volume":"93","author":"Zuroff","year":"2012","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13036-015-0011-2","article-title":"Artificial Cell-cell Communication as an Emerging Tool in Synthetic Biology Applications","volume":"9","author":"Hennig","year":"2015","journal-title":"J. Biol. Eng."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nature09326","article-title":"Functional Roles for Noise in Genetic Circuits","volume":"467","author":"Eldar","year":"2010","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nrm3064","article-title":"Asymmetric Cell Division in Land Plants and Algae: The Driving Force for Differentiation","volume":"12","author":"Smet","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Naldi, A., Carneiro, J., Chaouiya, C., and Thieffry, D. (2010). Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modelling. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000912"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.stemcr.2014.02.009","article-title":"Cell-Cycle Control of Developmentally Regulated Transcription Factors Accounts for Heterogeneity in Human Pluripotent Cells","volume":"2","author":"Singh","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20182495","DOI":"10.1098\/rspb.2018.2495","article-title":"Force-based Three-Dimensional Model Predicts Mechanical Drivers of Cell Sorting","volume":"286","author":"Revell","year":"2019","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1021\/sb400030p","article-title":"Cell Polarity-Driven Instability Generates Self-Organized, Fractal Patterning of Cell Layers","volume":"2","author":"Rudge","year":"2013","journal-title":"ACS Synth. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1574-6941.2009.00745.x","article-title":"Cell-cell Signalling in Bacteria: Not Simply a Matter of Quorum","volume":"70","author":"Boyer","year":"2009","journal-title":"FEMS Microbiol. Ecol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1038\/ismej.2015.208","article-title":"Resource Limitation Drives Spatial Organization in Microbial Groups","volume":"10","author":"Mitri","year":"2015","journal-title":"ISME J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1242782","DOI":"10.1126\/science.1242782","article-title":"Secreting and Sensing the Same Molecule Allows Cells to Achieve Versatile Social Behaviors","volume":"343","author":"Youk","year":"2014","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cels.2015.10.012","article-title":"Molecular-Level Tuning of Cellular Autonomy Controls the Collective Behaviors of Cell Populations","volume":"1","author":"Maire","year":"2015","journal-title":"Cell Syst."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1073\/pnas.0305937101","article-title":"The Yeast Cell-cycle Network is Robustly Designed","volume":"101","author":"Li","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-5193(03)00035-3","article-title":"The Topology of the Regulatory Interactions Predicts the Expression Pattern of the Segment Polarity Genes in Drosophila melanogaster","volume":"223","author":"Albert","year":"2003","journal-title":"J. Theor. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Davidich, M.I., and Bornholdt, S. (2008). Boolean Network Model Predicts Cell Cycle Sequence of Fission Yeast. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001672"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/224177a0","article-title":"Homeostasis and Differentiation in Random Genetic Control Networks","volume":"224","author":"Kauffman","year":"1969","journal-title":"Nature"},{"key":"ref_49","unstructured":"Berg, H.C. (1993). Random Walks in Biology, Princeton University Press. [New and Expanded ed.]."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1093\/bioinformatics\/btu498","article-title":"Biocellion: Accelerating Computer Simulation of Multicellular Biological System Models","volume":"30","author":"Kang","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"138102","DOI":"10.1103\/PhysRevLett.121.138102","article-title":"Criticality Distinguishes the Ensemble of Biological Regulatory Networks","volume":"121","author":"Daniels","year":"2018","journal-title":"Phys. Rev. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Balleza, E., Alvarez-Buylla, E.R., Chaos, A., Kauffman, S., Shmulevich, I., and Aldana, M. (2008). Critical Dynamics in Genetic Regulatory Networks: Examples from Four Kingdoms. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002456"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1083\/jcb.201506106","article-title":"Tissue Patterning and Cellular Mechanics","volume":"211","author":"Heller","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Martinez-Sanchez, M.E., Mendoza, L., Villarreal, C., and Alvarez-Buylla, E.R. (2015). A Minimal Regulatory Network of Extrinsic and Intrinsic Factors Recovers Observed Patterns of CD4+ T Cell Differentiation and Plasticity. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004324"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.biosystems.2016.03.002","article-title":"Relative Stability of Network States in Boolean Network Models of Gene Regulation in Development","volume":"142\u2013143","author":"Zhou","year":"2016","journal-title":"Biosystems"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fgene.2020.00040","article-title":"A Computational Model of the Endothelial to Mesenchymal Transition","volume":"11","author":"Weinstein","year":"2020","journal-title":"Front. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"110031","DOI":"10.1016\/j.jtbi.2019.110031","article-title":"Cell Differentiation: What Have We Learned in 50 Years?","volume":"485","author":"Newman","year":"2020","journal-title":"J. Theor. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"ra54","DOI":"10.1126\/scisignal.2001763","article-title":"Yeast Dynamically Modify Their Environment to Achieve Better Mating Efficiency","volume":"4","author":"Jin","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1126\/science.1200037","article-title":"Dynamics of Dpp Signaling and Proliferation Control","volume":"331","author":"Wartlick","year":"2011","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4572","DOI":"10.4049\/jimmunol.0803900","article-title":"NK Cell Responsiveness Is Tuned Commensurate with the Number of Inhibitory Receptors for Self-MHC Class I: The Rheostat Model","volume":"182","author":"Joncker","year":"2009","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1049\/iet-syb.2010.0039","article-title":"Cell-cell Interaction and Diversity of Emergent Behaviours","volume":"5","author":"Damiani","year":"2011","journal-title":"IET Syst. Biol."}],"container-title":["Entropy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1099-4300\/25\/2\/319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:28:39Z","timestamp":1760120919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1099-4300\/25\/2\/319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":61,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["e25020319"],"URL":"https:\/\/doi.org\/10.3390\/e25020319","relation":{},"ISSN":["1099-4300"],"issn-type":[{"type":"electronic","value":"1099-4300"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}