Agent Based Modelling Helps in Understanding the Rules by Which Fibroblasts Support Keratinocyte Colony Formation 英文参考文献.docVIP

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Agent Based Modelling Helps in Understanding the Rules by Which Fibroblasts Support Keratinocyte Colony Formation 英文参考文献.doc

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Agent Based Modelling Helps in Understanding the Rules by Which Fibroblasts Support Keratinocyte Colony Formation 英文参考文献

AgentBasedModellingHelpsinUnderstandingthe RulesbyWhichFibroblastsSupportKeratinocyteColony Formation TaoSun1*,PhilMcMinn2,MikeHolcombe2,RodSmallwood2,SheilaMacNeil1* 1DepartmentofEngineeringMaterials,UniversityofSheffield,Sheffield,UnitedKingdom,2DepartmentofComputerScience,UniversityofSheffield,Sheffield,United Kingdom Abstract Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinicaluse.Withgrowingconcernsaboutthesafetyofthesexenobioticmaterials,itisdesirabletoculturekeratinocytesin mediawithoutanimalderivedproducts.Animprovedunderstandingofepithelial/mesenchymalinteractionscouldassistin this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocytecolonyformationmodeltoincludetheresponseofkeratinocytestobothfibroblastsandserum.Themodel wasvalidatedbycomparisonoftheinvirtuoandinvitromulticellularbehaviourofkeratinocytesandfibroblastsinsingle andco-cultureinGreensmedium.Totesttherobustnessofthemodel,severalpropertiesofthefibroblastswerechangedto investigatetheirinfluenceonthemulticellularmorphogenesisofkeratinocyesandfibroblasts.Themodelwasthenusedto generatehypothesestoexploretheinteractionsofbothproliferativeandgrowtharrestedfibroblastswithkeratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblaststokeratinocyteswouldcriticallyinfluencekeratinocytecolonyexpansion,2)thisrationeededtobeoptimumat the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytesand4)inthepresenceofanadequatenumberoffibroblasts,keratinocyteexpansionwouldbeindependent ofserum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this stu