組織生物學(xué)：尋找新范式 Tissue Biology - In Search of a New Paradigm

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AnnualReviewofCellandDevelopmentalBiology

TissueBiology:InSearchofaNewParadigm

MiriAdler,1,2,*ArunR.Chavan,2,*andRuslanMedzhitov1,2,3

1TanenbaumCenterforTheoreticalandAnalyticalHumanBiology,YaleUniversitySchoolofMedicine,NewHaven,Connecticut,USA;email:

ruslan.medzhitov@

2DepartmentofImmunobiology,YaleUniversitySchoolofMedicine,NewHaven,Connecticut,USA

3HowardHughesMedicalInstitute,YaleUniversitySchoolofMedicine,NewHaven,Connecticut,USA

Keywords

celltype,tissueorganization,tissuemodules,cellrelations,cellcategories,evolution,self-organization

Abstract

Animaltissuesaremadeupofmultiplecelltypesthatareincreasinglywell-characterized,yetourunderstandingofthecoreprinciplesthatgoverntissueorganizationisstillincomplete.Thisisinpartbecausemanyobserv-abletissuecharacteristics,suchascellularcompositionandspatialpatterns,areemergentproperties,andassuch,theycannotbeexplainedthroughtheknowledgeofindividualcellsalone.Hereweproposeacomplexsystemstheoryperspectivetoaddressthisfundamentalgapinourunderstandingoftissuebiology.Weintroducetheconceptofcellcategories,whichisbasedoncellrelationsratherthancellidentity.Basedonthesenotionswethendiscusscommonprinciplesoftissuemodularity,introducingcompositional,structural,andfunctionaltissuemodules.Celldiversityandcellrelationsprovideabasisforanewperspectiveontheunderlyingprinciplesoftissueorganizationinhealthanddisease.

Annu.Rev.CellDev.Biol.2023.39:67–89

FirstpublishedasaReviewinAdvanceonAugust22,2023

TheAnnualReviewofCellandDevelopmentalBiologyisonlineat

/10.1146/annurev-cellbio-120420-

113830

Copyright?2023bytheauthor(s).Thisworkis

licensedunderaCreativeCommonsAttribution4.0InternationalLicense,whichpermitsunrestricted

use,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Seecreditlinesofimagesorotherthird-party

materialinthisarticleforlicenseinformation.

*Theseauthorscontributedequallytothisarticle

Contents

INTRODUCTION 68

TISSUEORGANIZATIONTHROUGHANIMALEVOLUTION 69

CELLTYPESANDTHEIREVOLUTION 71

CELLCATEGORIESBASEDONCELLRELATIONS 72

Primary-SupportiveRelation 72

ComplementarityRelation 73

InstructiveRelation 74

Supplier-ConsumerRelation 75

HierarchicalRelation 75

MutualExclusivity 76

MODULARORGANIZATIONOFTISSUES:MINIMALTISSUEUNITS

ANDHIGHER-ORDERMODULES 76

CompositionalTissueModules 76

StructuralTissueModules 77

FunctionalTissueModules 78

SELF-ORGANIZATION,EMERGENCE,ANDSIMPLERULES 79

RULESOFCELLCOMMUNICATION 81

FunctionalDemandandtheControlofGFProduction 81

ExtracellularMatrixandStigmergy:BuildingandInterpreting

theCellularEnvironment 82

WHATCANGOWRONGANDWHY? 84

CONCLUSIONSANDPERSPECTIVES 84

INTRODUCTION

Tissuesareusuallydefinedascollectionsofcellswithsharedmorphologyandfunction.Acanon-icalviewisthattherearefourmaintypesofanimaltissues:epithelial,connective,muscle,andnervous.However,inmanycontextsitismorenaturaltothinkoftissuesasorganizedassem-bliesofdifferentcelltypes.Withtherecentgrowthininterestintissuebiology,itcanbearguedthatsomeofthebasicnotionsinthatfieldneedtobereframedfromthemodernperspectivetomaketheminternallyconsistent,generalizable,andinformative.Inparticular,thiswillhelpad-dresssomeofthefundamentalgapsinourunderstandingofbiologyatthetissuelevel.Theseincludebasicquestionsabouttissueorganization:Whatarethedesignprinciplesoftissuearchi-tecture?Dodifferenttissuesrepresentvariationsonacommontheme,similartodifferentcelltypesbeingvariationsonthebasicdesignofaeukaryoticcell?Istheresomesortofhierarchyofcelltypeswithintissues?Ifso,whatisitbasedon?Answeringthesekindsofquestionswouldrequiredevelopinganewconceptualframeworkandapplyingperspectivesfromotherfieldswithabetterunderstandingofrelatedproblems.This,inturn,requiresacertainlevelofabstractionandformalism,freedfromfield-specificjargon,sothatourunderstandingoftissuebiologycouldbebuiltfromfirstprinciples.

Oneperspectivethatisparticularlyrelevanttotissuebiologycomesfromcomplexsystemstheory(

Miller&Page2007

,

Solé&Goodwin2000

).Acomplexsystemisdefinedasacollectionofdiverse,interdependent,andinterconnectedagentsthatinteractwitheachotheraccordingtosomerules.Aconsequenceoftheseinteractionsisemergentpropertiesofthesystem(itsstructure,

68Adler?Chavan?Medzhitov

function,ordynamicbehavior),whicharenotreducibletothecharacteristicsofindividualagents.Tissueshaveallthefeaturesofacomplexsystem:Theyarecomposedofdiverse,interconnected,andinterdependentcelltypesthatinteractwitheachotheraccordingtosomerules,resultinginemergentpropertiesoftissuestructure,function,andcomposition.

Herewediscussbasicaspectsoftissuebiologyfromacomplexsystemsperspective.Wefirstreviewthegenerationofcelltypediversityduringevolution.Diversityhastwofaces:Intrinsicdiversityreflectscellidentity,includingcelltypes,subsets,andstates.Extrinsicdiversityisdefinedbycells’relationstoeachother.Theserelationsdefinecellcategories,justasthecategoriesparentandfriendaredefinedbytherelationsbetweenpeopleregardlessoftheiridentities.Wethendiscussthepossiblemodularunitsoftissueorganization,includingcompositional,functional,andstructuralunits.Finally,weexplorepossiblerulesofcellinteractions,leadingtoself-organizationandemergentproperties.

TISSUEORGANIZATIONTHROUGHANIMALEVOLUTION

Majoreventsintheevolutionofanimaltissuesandbodyplansoccurreddeepintheanimalphylogeny.Themorerecentchangesentailedelaborationsofthepreexistingframeworkoftissuetypes,forexample,theevolutionofabrainbythecentralizationofthenervoussystemthatoriginatedmuchearlierinmetazoanevolution.Tracingtheevolutionoffoundationalanimaltissuetypes,therefore,requiresustoinferthetissuecompositionoftheurmetazoanancestor(thehypotheticalmostrecentcommonancestorofallmetazoans)andtheearlyeventsinmetazoanevolution.

Metazoaconsistsoffivemajorlineages:Bilateria,Cnidaria,Ctenophora,Placozoa,andPorifera

(Dunnetal.2014

).BilateriaandCnidariaaresisterlineages,butthephylogeneticrelationshipsamongtherestofthelineagesarenotfullyresolved.WhilethereisaccumulatingevidencesupportingtheCtenophora-sistermodel(

Lietal.2021

,

Whelanetal.2015

)incontrasttothetraditionalPorifera-sistermodel,theresolutionoftherootoftheanimaltree—whichiscrucialforinferringurmetazoantraits—remainsdebated(

Telfordetal.2016

).Despitethisuncertainty,wecanstillinfertheancestralstatesofmostanimaltissues,althoughwithvaryingdegreesofconfidence(

King&Rokas2017

).

Thepresenceoftheepitheliallayerinallfivemajorlineagesofanimals(

Figure1

)suggeststhatitisafoundationalmetazoantissuethatlikelyexistedintheurmetazoanancestor(

Leys&

Riesgo2012

).Consistentwiththeancientoriginoftheepithelium,inklingsoffeaturesassociatedwithepithelialcellsareseeneveninunicellularrelativesofanimals.Forexample,thegenesin-volvedincell-celladhesioncomplexes,aswellasthemaincomponentofthebasementmembrane,CollagenIV,predatemetazoansandarepresentinunicellularholozoans(

Grau-Bovéetal.2017

,

Milleretal.2013

).Additionally,facultativelymulticellularstagesinunicellularholozoanssuchaschoanoflagellatesformasasinglelayerofpolarizedcellssimilartoanepithelium(

Brunet&King

2017

),highlightingtheroleofepithelialcellsindefininganorganism’sboundary,makingthemtheessentialtissuetypeinanimals.

Epithelial-mesenchymalunitsaretheelementalbuildingblocksofmostanimaltissues.Indeed,inadditiontotheessentialepithelialtissue,amesenchymalcelltypeispresentinallanimals:forexample,archaeocytesinsponges(

Pechenik2015

),fibercellsinplacozoans(

Smithetal.2014

),andfibroblastsinvertebrates.Thetimingoftheoriginofmesenchymalcellswasuncleargiventhattheclosestlivingrelativesofanimals,choanoflagellates,exhibitanepithelial-likepolarizedcellphenotype.However,

Brunetetal.(2021)

recentlyshowedthatchoanoflagellatestransitiontoanamoeboidstateinresponsetostress,suggestingthatthemesenchymalphenotype,aswellasamechanismofepithelial-mesenchymaltransition(EMT),alreadyexistedintheurmetazoan

?TissueBiology:InSearchofaNewParadigm69

.Neurons

.Musclecells

.Mesenchymalcells.Epithelium

Figure1

Absent

AbsentbutfunctionpresentPresent

Ctenophora

Porifera

Placozoa

Cnidaria

Bilateria

PhylogeneticdistributionofmajortissuesandcelltypesacrossMetazoa.Epithelialandmesenchymalcellsarepresentinallanimallineages,suggestingtheancientoriginofaminimalepithelial-mesenchymaltissueunitinanimals.Silhouettesarefrom

.

ancestor.Theancientoriginofboththeepithelialandmesenchymalcellsfurthersupportsthecentralityoftheepithelial-mesenchymalunitinanimaltissueorganization.

Beyondtheepithelial-mesenchymalunit,ctenophores,cnidarians,andbilaterianshavespecial-izedmusclecells,whilePoriferaandPlacozoalackspecializedmusclecellsbutsomeoftheircelltypesarecontractile(

Pechenik2015

).Thus,althoughmyocytesarenotasharedfeatureofanimals,thecontractileapparatusis.Theinferenceoftheancestryofmyocytesreliesontheresolutionoftherootoftheanimaltree,butitisparsimonioustoreasonthattheurmetazoanancestorhadacontractilecelltype,oratleastthecontractilemachinery.

Inferenceoftheevolutionofneuronaltissuealsoreliesontheresolutionofthesponge-ctenophorecontroversybecausespongesandplacozoansdonothaveanervoussystem.However,celltypesexpressingneuronalmodules,suchasthepresynapticandpostsynapticmachinery,havebeenidentifiedinsponges(

Musseretal.2021

);andpeptidergicneurosecretorycellsthatlikelyregulatefeedingandlocomotionhavebeenidentifiedinplacozoans(

Pechenik2015

,

Smithetal.

2014

).Interestingly,ctenophoreneuronsaredistinctfromneuronsinotheranimals(

Burkhardt

2022

,

Sebe-Pedrosetal.2018

),raisingthepossibilitythatthenervoussystemsofctenophoresandofotheranimalsmayhaveevolvedconvergently(

Moroz2015

).Theseobservationstogetherimplyadeephomology(

Shubinetal.2009

)ofnervoussystemsinanimals.Thatis,whiletheurmetazoanancestorlackedanervoussystem,ithadfunctionalandregulatorymodulesthatcreatedthepreconditionsfor,andinparallelevolvedinto,thenervoussystemsinCtenophora,Cnidaria,andBilateria.

Insummary,theurmetazoanancestralbodyplanwaslikelyboundedbyanepitheliallayer,perhapswithamesenchymalamoeboidcelltypeinthespacebetweentheepitheliallayers.Theepithelialtissuewaslikelymultifunctionalandperformedcontractileaswellassensoryandregulatoryfunctions.

70Adler?Chavan?Medzhitov

CELLTYPESANDTHEIREVOLUTION

Theinferredtissuecompositionoftheurmetazoanancestorindicatesthatthefundamentaltis-suetypesandcelltypefamiliesaroseearlyinanimalevolutionandsubsequentlyunderwentlineage-specificexpansion.Theprogressiveexpansionoftissuetypeslikelyoccurredthroughthediversificationofcelltypes(

Arendtetal.2016

)andtheevolutionofinteractionsamongthem.

Thecelltypesintheurmetazoanancestorwerelikelymultifunctional(

Arendt2008

),e.g.,ep-ithelialcellspossessingcontractilemachinery,whichprogressivelydiversifiedintofunctionallyspecializedcelltypes.Thisimpliesthattheincreaseinmorphologicalcomplexityovertimeinmetazoanlineagesdoesnotnecessarilyreflectanincreaseinfunctionalcomplexity.Makingacleardistinctionbetweenthetwoenablesustoconceptualizeamodelofcelltypediversifica-tionwithatwo-stepprocess:theadditionofanewfunctiontoanexistingcelltype(increaseinfunctionalcomplexity)followedbythesegregationoffunctionsintotwosistercelltypes(increaseinmorphologicalcomplexity).

Belowwedescribeamodelthatoutlinestwomodesbywhichacelltypecanevolveintotwosistercelltypes.Thetwomodescanbesummarizedasaninduced-to-constitutivetransition

(Figure2a

)andtrade-offresolutionbydivisionoflabor(

Figure2b

),andtheyaremotivatedbythetemporal-to-spatialtransitionanddivisionoflabormodelsproposedfortheoriginofanimalmulticellularity(

Brunet&King2017

).

Inthefirstmodeofcelltypogenesis,thenewfunctionisdrivenbyageneexpressionprogramthatisinducedbyanenvironmentalcue,whichcanbeeitherachemicalsignalorapositionalsignalbasedonthecell’sanatomicallocation(

Okabe&Medzhitov2016

).Atfirst,thisinducedstatecanbeareversibleactivationorpolarizationstate.Subsequently,theinducedgeneexpressionprogramcanevolvetobeconstitutive.Thisisakintogeneticassimilation(

Waddington1942

,

1953

)andcanhappenmechanisticallybybringingtheexpressionoftheinducibletranscriptionfactorunderthecontrolofthelineage-definingtranscriptionfactors(

Pope&Medzhitov2018

).Inotherwords,

aInduced-to-constitutivetransitionbTrade-ofresolutionbydivisionoflabor

AGenetic

ASegregationofgene

assimilation

expressionprograms

aaDO.

ArchetypeA

ArchetypeB

A

Irreversibletransition

AContinuumofvariation

duetotrade-ofs

Environment

A

AOriginofanew

function(induced)

Originofanew

function(constitutive)

Increasein

morphologicalcomplexity

Increaseinfunctionalcomplexity

Figure2

Twomodesofcelltypediversificationinevolution.Thecolorsindicatethefunctionperformedbythecell

type.(a)Induced-to-constitutivetransition.(b)Trade-offresolutionbydivisionoflabor.

?TissueBiology:InSearchofaNewParadigm71

celltypediversificationtakesplaceviathedevelopmentalindividuationofthealternativestatesoftheancestralcelltype.Thisisexemplifiedbytheco-optionofanancestralstressresponseintheoriginofanovelcelltype(

Love&Wagner2022

),forexample,thedecidualstromalcellsinplacentalmammals(

Erkenbracketal.2018

)andpossiblythemetazoanmesenchymalcells(

Brunet

etal.2021

).

Inthesecondmodeofcelltypogenesis,thenewfunctionisaddedtotheancestralcelltypeasanewfunctionalmodulethatisconstitutivelyexpressed.Therefore,thetwofunctionsoftheancestralcelltypearenottemporallyorspatiallydelineatedbutareperformedbythesamecell.Dependingonthenatureofthefunctions,suchmultifunctionalitycanresultintrade-offsbetweenthetwofunctionssuchthatanindividualcellcanperformonefunctioneffectivelyonlyattheex-penseoftheotherfunction.Anaturaloutcomeofsuchatrade-offisthatindividualcellsofthegivencelltypeprefertoperformonefunctionovertheother,resultinginacontinuumofvaria-tion(infunctionaswellasgeneexpression)amongthecellsofthegiventype.Theverticesortheextremepositionsofthecontinuousspaceoccupiedbytheindividualsofthiscelltypeingeneex-pressionspacerepresenttheso-calledarchetypesofthegivencelltypethatprioritizeonefunctionovertheother(

Adleretal.2019

,

2023

;

Hartetal.2015

;

Koremetal.2015

).Thetrade-offscanberesolvedovertimebyexaggeratingthecontinuumofvariation,turningoffthegeneexpressionprogramforonefunctionandbecomingfunctionallyspecializedbyselectivelyretainingthegeneexpressionprogramfortheotherfunction.Inthismode,thedifferentarchetypescanbeviewedasprecursorsofnewspecializedcelltypes.Forexample,osteoblasts,stemcells,andadipocytescanbeviewedasspecialistcellsevolvingfrommesenchymalprecursorcellsthatfacedatrade-offbetweenextracellularmatrix(ECM)secretion,growthfactor(GF)production,andtriglyceridestorage,re-spectively.Theexistenceofcelltype–specificarchetypeshasbeenfurtherdemonstratedinhealth

(Adleretal.2019

,

2023

)anddisease(

Cook&Wrana2022

,

Friedmanetal.2020

,

Grovesetal.

2021

,

Hausser&Alon2020

,

Hausseretal.2019

).Anotherwayofresolvingtrade-offsisbyusingatemporaldivisionoflaborthatisgovernedbycircadianclocks(

Partchetal.2014

).

CELLCATEGORIESBASEDONCELLRELATIONS

Thenotionofacelltypereflectsintrinsiccharacteristicsofcells,includingtheirdevelopmentalorigin,function,andmorphology.Tounderstandcellsintheirsocialcontext,weneedacomple-mentarycharacteristicthatreflectsthepatternsofcells’relationstoeachother.Relationsdefinecellcategoriesthatdonotnecessarilycorrespondtotheiridentities(orcelltypes).Thedifferencesinclassificationsthatarebasedonidentityversusrelationscanbeillustratedusingasocialsystemasananalogy:Understandingthebehaviorofasocialgroupusinginformationaboutindividualfeatures(e.g.,names,age,sex,andprofession)aloneislimiting.Knowinghowdifferentindividualsrelatetoeachother(e.g.,parent-child,employer-employee,spousal,andfriendshiprelations)isessentialtotheunderstandingofthesocialstructure.Theserelationsdefinecategoriesofspouses,parents,employees,orfriends,andtheyprovideaninsightintotheorganizationofasocialgroupthatisnotavailablefromtheknowledgeofindividualcharacteristicsalone.

Similarly,characterizingcellsbasedontheirindividualcelltypepropertiesisinsufficientforunderstandingtheirroleintissueorganization.Toexplorecellsintheirsocialcontext,wehavetodefinecellcategorieswheretherelevantattributeisnotthecell’sidentitybutratheritsrelationstoothercells(

Figure3

).Belowwediscussseveralexamplesofcommoncellrelationsandtheirrolesintissueorganization.

Primary-SupportiveRelation

Consideringthefunctionalorganizationoftissues,thediversityofcelltypescanusuallybedi-videdintotwofunctionalcategories:cellsperformingprimaryfunctionsofthetissueandcells

72Adler?Chavan?Medzhitov

aCelltypeparadigmbCellrelationparadigm

CelltypeACelltypeB

CelltypeC

CelltypeD

CellrelationA

CellrelationBCellrelationC

Figure3

Tissueorganizationbasedoncelltypesandcellrelations,showingaschematicofatissuewherecellsarecategorized(a)basedontheirtypeand(b)basedontheirrelationtoothercells.

performingsupportivefunctionsthatfacilitateandoptimizetheperformanceoftheprimarytis-suefunction(

Meizlishetal.2021

,

Okabe&Medzhitov2016

)(

Figure4a

).Primary-supportivecellrelationsappearedearlyinanimalevolutionasseenintheprimordialepithelial-mesenchymaltissueunit,whereepithelialcellsperformtheprimaryfunctionsofdefense,nutrientacquisition,andmaintenanceofinternalhomeostasis,whereasmesenchymalcellsprovidestructuralandfunc-tionalsupportbytheproductionoftheECMandothersecretedfactorsthatsupportepithelialcells’primaryfunctions.

Aprimary-supportiverelationisalsofoundbetweenneuronsandSchwanncells(

Gilbert2010

)wheretheroleofSchwanncellsistofacilitatethefunctionofneurons.Similarly,pericytessupportthefunctionofendothelialcells,andastrocytesprovidemetabolicandothersupportivefunctionstoneuronsinthebrain.

Tissue-specificfunctionsareperformedbytheprimarycelltypesthatvaryacrossdifferenttissues,whilesupportivecellscanbeeitherspecialized(asexemplifiedbyglialcellsinthebrainorpericytesinbloodvessels)oruniversaltomosttissues.Thelatterincludefibroblasts,capillaryendothelialcells,andtissue-residentmacrophages.Atleastinvertebrates,thesecelltypesper-formessentialsupportivefunctions,includingECMproduction,oxygenandnutrientdelivery,andmaintenanceoftissuehomeostasis,respectively.

Thedefinitionofprimary/supportivefunctionsisnotabsolutebutisdependentonthescaleatwhichweareexaminingthesystem(

Meizlishetal.2021

).Forexample,themainfunctionsoftheintestinalepitheliumaredigestionandabsorption,whichareprimaryfunctionsatthetissuelevelbutsupportiveattheorganismallevel,providingnutrientstotheorganismasawhole.Im-muneprimarydefensefunctionsattheimmunesystemlevelaresupportiveattheorganismallevel.Germlinecellsaretheultimateprimarycellsthatarecrucialforreproductivesuccess,whereassomaticcellsprovidesupportbyallowinggermlinecellstopropagatetothenextgeneration.

ComplementarityRelation

Theprimary-supportiverelationdescribedaboveisanexampleofanasymmetricrelation:CellAissupportiveforcellBbutnotviceversa.However,therearesituationswherethefunctionaldivisionoflaborintissuesresultsincellsequallycontributingtoaprimaryfunction—wheretheycomple-menteachother’sfunctionbyformingfunctionalunits(

Figure4b

).Forexample,osteoblastsandosteoclastshavecomplementaryfunctionsinmatrixdepositionandresorption(

Kimetal.2020

),asdofibroblastsandmacrophagesingeneral(

Meizlishetal.2021

).Thecolumnarandbulboussecre-torycellsoftherovebeetles’tergalglandproducethesolventandbenzoquinones,respectively,

?TissueBiology:InSearchofaNewParadigm73

CELLRELATION

aPrimary-supportiverelation

bComplementarityrelation

FunctionA

Environment

cInstructiverelation

Efector

Growthfactor

dSupplier-consumerrelation

Asymmetric

Tcell

Mastcell

eHierarchicalrelation

Stromal

(e.g.,ibroblast)Epithelial

CapillaryMacrophage

endothelium

fMutualexclusivity

or

FunctionA(supportive)

CelltypeA

FunctionB(primary)

CelltypeB

▲

AdipocyteSmoothmuscle

CelltypeA

SupplierConsumer

Cell-fatechoices

Signal

DESCRIPTION

provision

CelltypeB

Symmetric

Sensor

Functional

Existential

Information

dependency

dependency

dependency

Figure4

Summaryofcellrelationsthatareuniversallyfoundacrossanimaltissues.Thehierarchicalrelationinpaneleillustratesapyramidofcellhierarchicalrelationsinvertebrates.

thattogetherconstitutethedefensivecompoundssecretedbythegland(

Brückneretal.2021

).Functionalunitsarealsoformedbymotorneuronsandskeletalmusclecells.

InstructiveRelation

Theprimordialepithelial-mesenchymaltissueunitdefinesanothercellrelationthatdependsonasymmetricinformationtransfer.Duringembryonicinduction,mesenchymalcellsproducein-structions,suchasbonemorphogeneticprotein(BMP)inhibitorsandfibroblastgrowthfactors

74Adler?Chavan?Medzhitov

(FGFs),thatactonWntresponsiveepidermalcellsleadingtotheirdifferentiationintoplacodes

(Fuchs2007

,

Hsuetal.2014

).Here,dermalcellscontainpositionalinformation,whileepider-malcellshaveseveralfatechoices(e.g.,toformdifferentskinappendages,dependingontheirpositionalongbodyaxes).Thefatechoiceofepidermalcellsisdictatedbysignalsderivedfromdermalcells,whichinturnaredeterminedbypositionalinformation(expressionofspecificHoxgenesindermalcells)(

Chang2009

).Thisexampleillustratestheinstructiverelation:CellAhasinformationthatdictatesthefatechoicesofcellB(

Figure4c

).EithertheinformationcanpreexistincellA(asisthecasewithpositionalinformation)orcellAcanacquiretheinformationfromitsenvironment.Inthelattercase,theinstructiverelationbetweenAandBisequivalenttothefamiliarsensor-effectorrelationfoundinhomeostaticcircuits:Sensorcellsmonitorthevaluesofahomeostaticvariableandproducesignalsthatinstructeffectorcellstoalterthatvalueinthedesireddirection(

Kotas&Medzhitov2015

).Here,sensorcellshaveinformation(aboutthevalueofthevariable),effectorcellshavechoicestochangethatvalue,andtheactionofeffectorcellsisdictatedbythesignalproducedbysensorcells.Anotherexampleofinstructiverelationsisbetweennichecellsandstemcells:Here,nichecellscandictatethefateofstemcells,suchasself-renewalversusdifferentiation.Similarly,dendriticcellsdetectpathogensandproducecytokines(IL-12,IL-6,etc.)thatdictatedifferentiationofnaiveTcellsintospecificeffectorlineages(

Banchereau

etal.2000

).Inallthesecases,thereisasymmetricinformationtransferfromonecelltoanother.

Supplier-ConsumerRelation

ThenextcategoryofcellularrelationweconsiderisbasedonexistentialdependencybetweencellswherecellAdependsoncellBforexistenceinaparticulartissueniche.Similartotrophicrelationshipsbetweenorganismsinanecosystem,onecellmayrelyonresourcesprovidedbyan-othercelltosurvive.Theseresourcescanbelineage-restrictedGFs,metabolites,andothersignalsprovidedbysuppliercellsthatareessentialforthesurvivalofcellsconsumingthem.Anothertypeofexistentialdependencyiswhenonecelltyperegulatesthetissuemicroenvironmentsuchthatitispermissivefortheexistenceoftheothercelltype,asexemplifiedinhowECMpropertiesaffectcellattachmentandsurvival.Incontrasttothesensor-effectorrelation,whichisdefinedbyasymmetryofinformation,thisrelationisdefinedbyasymmetryofresources.

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