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LYMPHATICSTRUCTURE ANDFUNCTIONINHEALTH ANDDISEASE
LYMPHATICSTRUCTURE ANDFUNCTIONINHEALTH ANDDISEASE
Editedby
FELICITY N.E.GAVINS
DepartmentofLifeSciences,BrunelUniversityLondon, Uxbridge,UnitedKingdom
J.STEVE ALEXANDER
DepartmentofMolecular&CellularPhysiology,LSUHealthSciencesCenter, Shreveport,LA,UnitedStates
AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom
Copyright©2020ElsevierInc.Allrightsreserved.
PublishedincooperationwithTheInternationalSocietyforNeurovascularDisease.
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Notices
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Introduction/overview
FelicityN.E.Gavinsa,b,J.SteveAlexandera
aDepartmentofMolecularandCellularPhysiology,LSUHealthSciences Center,Shreveport,LA,UnitedStates
bBrunelUniversityLondon,KingstonLn,London,Uxbridge, UnitedKingdom
The lymphaticsystem consistsofthevascularnetworkoftissues andorgans(thelymphnodes,thymus,spleen,tonsils,andappendix)thatdraininterstitialfluid(lymph)fromtheperipheraltissue backtothebloodcirculation.Thelymphaticsystemformspartof thewell-described vascularsystem butisnota circulatorysystem as itisagroupofone-wayconduits.Thisincrediblycomplexnetwork ofvesselsnotonlycollectslymph,whichisanastoundingfeatatthe levelofphysics,butalsoplaysacrucialroleinourimmunesystem; itistheleastwellcharacterizedandoftenmalignedandmarginalizedvascularsystemreflectingthegreatdifficultyinvisualizing lymphaticsoutsideoftheconfinesofafat-mealconsumption,which necessitatedtheidentificationofmanymolecularmarkersthatdistinguishlymphaticendothelialcellsfromthebloodvascularendothelium.Consequently,therehasbeenmorerecentlyanexplosionof researchintothelymphaticsystemwiththeannualnumberofpublicationsonlymphaticsclimbingfrom2093in1990to5519in2015. Theliteratureisproceedingsoquicklythatwethoughtthatthisarea ofstudydeservedatthispointasummaryofhowlymphaticsand lymphaticendothelialcellscontributetothefunctioningofseveral differentorgansystemsandtohealthanddisease.
Thistextisthereforedevotedtotheevaluationofhowthelymphaticorganizationandsupplyinseveralorgansystemsmaycontributetohowtheseorgansfunctionandhowtheirdisturbancesin
structure,patterning,orfunctionmayleadtoorganstress.Themultifacetedrolesthatlymphaticsplayinhealthanddiseaseinclude contributionsgatheredfromleadingexpertsaroundtheworld whoareactivelyworkingintherapidlyexpandingfieldoflymphaticresearch.
ThelymphaticsystemwasfirstdescribedbyHippocratesofKos (c.460–377BC),andassuch,B.B.LeeandH.Suamihavefocusedon theevolutionandtheembryonicdevelopmentofthelymphaticsystemin Chapter2.Thisteamalsobringstogethertherecentadvance inthefieldof lymphangiogenesis,highlightingboththephysiological andpathologicalrolesplayedbylymphaticdevelopment.
Asmentionedearlier,thelymphaticsystemplaysakeyroleinthe immunesystem.In Chapter3,M.StephensandPierre-Yvesvonder Weidfocusontherolethatlymphaticvesselsandlymphaticcontractionsplayinedemaresolutionandimmunecelltrafficking, especiallyinthecontextoftheintestineandinflammatoryprocesses associatedwiththegastrointestinaltract.Stephensandvonder Weiddiscusstheimplicationsandsignificanceoflymphnodeswelling(lymphadenopathy),whichoccursininflammation,infection,and diseases.Finally,thischapterdiscussesthedysfunctionoflymphaticvesselfunctioninavarietyofpathologies(oftenassociated withchronicinflammation)suchasrheumatoidarthritisandosteoarthritis,elephantiasis,inflammatoryboweldiseases,metabolic syndromeanddiabetes,andcancer,coupledwithdiscussions regardingtheconsequencesoftargetinglymphaticpumpfortherapeuticbenefits.
Next,wemovetothehydrodynamicregulationoflymphaticvesseltransportandtheimpactthataginghasontheseevents (Chapter4).Inthischapter,A.A.GashevandD.C.Zawiejadiscuss theconceptsofintrinsicandextrinsiclymphpumps,alongwith thejobthattheyplayinmodulatinglymphaticvesselcontractility. Theywilldiscussthenovelregulatoryfunctionofhistamineasan endothelium-derivedrelaxingfactor(EDRF).Additionally,while theimportantrolethattheagingprocessplaysinandtheimpactit hasonthevascularsystem(termed vascularaging)arerecognized, verylittleisknownwithrespecttolymphaticsystemandagingassociatedchangesintheactivelymphpumps.Assuch,A.A.Gashev andD.C.Zawiejawilldiscusstheseissuesindetail,bringingtogether theirownworkandthatofthescientificcommunity.
Thebrainisresponsiblefor25%ofthebody’smetabolism,even thoughitonlyencompasses2%ofthebody’stotalmass.Aswiththe restofthebody,metabolismleadstothegenerationofwasteproductsthatneedtobecleared,anditisparticularlyimportantwhenit comestothebrainthatthisclearancemechanismisefficientand effective.Therefore, Chapter5 concentratesonthelymphaticsystem inthecontextofthecentralnervoussystem(CNS).J.W.Yunetal. discussthethreedifferentbrainlymphaticclearancepathwaysthat arecurrentlydescribed,thatis,(i)theperivascularpathway,(ii)the glymphaticpathway,and(iii)themeningealpathway.Thesedifferentpathwaysandtherolethattheyplayindiseasesandconditions oftheCNS,suchasAlzheimer’sdisease(AD),multiplesclerosis (MS),andcerebralischemia(stroke),arereviewedatlength.Asdiscussedinthepreviouschapter(Chapter4),agingisasignificantcontributingfactortoperipheralimmuneresponses;additionally,it alsoplaysaconsiderableroleincentralimmuneresponses,incorporatingboththeglymphaticsystemandbrainlymphaticvasculature. Chapter5 willdeliberateaginginthecontextoftheCNSandthe lymphaticsystemandhowtheCNSlymphaticscanbeexploited fordrugdiscoveryprogramstoidentifynewtherapeutictargets forthetreatmentofneurovascularandneurodegenerative disorders.
MovingonfromtheCNS,inthenextchapter(Chapter6),B.B.Lee andM.Amoreweighupthedefectivedevelopmentofperipheral lymphaticsystem(termed lymphaticmalformation (LM)),whichis oneofthevariousformsof congenitalvascularmalformations (CVMs) butonlyaffectsthelymphaticcirculation.ItisknownthatLMscan presentclinicallyasasolitary/independentlesionorcoexistwith otherCVMs,oftenasa hemolymphaticmalformation (HLM).Notonly dotheauthorsdiscussLMsindetail,butalsotheyprovideclinical andmanagementoptionsforpatientswith,forexample,KlippelTrenaunaysyndrome.
In Chapter7,thelymphaticsoftheheartarereviewedby J.S.AlexanderandJ.W.Yun.Theheartisadynamicorganinterms ofitsmechanicalpropulsionofthebloodflow,andassuch.Itslymphaticsystemhaslongremainede nigmatic.J.S.Alexanderand J.W.Yundiscusstheoriginsanddevelopmentofcardiaclymphatics,patterning,andfunctioning,placingparticularemphasis ontherolesthatthecardiaclymphaticsmayplayinclinical
conditionsrangingfromsurgically inducedlymphaticdistress,to myocardialinfarction,tohearttransplantation.
Inthefinalchapterofourbook(Chapter8),A.Mohretal.focuson theconceptofthesurgicalapproachoflymphaticreconstruction, whichiscommonlyusedforpatientswithdestructedorobstructed lymphaticvesselswhoaresufferingfromsecondarylymphedema. Amainadvantageofthissurgicalapproachisthatitallowsfor additionaltreatmentoptionsfortheconditionofsecondarylymphedemaespeciallyifpatientsareresistanttoconservativetherapy. However,aswitheveryintervention,thereareprosandcons,which A.Mohretal.discussindetailinthischapter,alongwiththehistory ofsurgicalapproachesforlymphaticreconstruction.
Wehopethisvolumeservesasastartingpointforreadersboth scientificallyandmedicallymindedalikeatthelevelofstudents tomoreadvancedreaders.Here,wehavebeguntoconsiderhow thisoftennearlyinvisible,parallelsistertothecirculatorysystem supportsthebloodvasculature,accomplishingsomanydiverse functionsthatareonlyrecognizedwhenlymphaticdysfunction occurs.Therecognitionthatlymphaticsmaycontributetomany clinicalconditionsopensvastnewvistasforthedevelopmentof therapiesthatexploitnewfindings,mechanisms,andreagentsactingonthelymphaticvasculature.
Finally,wewouldliketothankKristiandMelanieatElsevierfor theirpatience,encouragement,andsupport.Inaddition,wethank alltheauthorsandreviewerswithoutwhomthisbookwouldnot havebeenpossible.
Ontogenyandphylogenyof lymphatics:Embryological aspect
B.B.Leea,HSuamib
aVascularSurgery,GeorgeWashingtonUniversityHospital,Washington, DC,UnitedStates
bAustralianLymphoedemaEducation,ResearchandTreatment,Macquarie University,Sydney,Australia
Historicalbackground
ThelymphaticsystemwasfirstdescribedbyHippocratesin 460–377BCas“whiteblood”basedonobservationof“chyle,”atype oflymphformedinthedigestivesystemthatistransportedthrough specializedlymphvesselsknownaslacteals [1,2].Heidentifiedthe lymphaticsystemcorrectlyasoneofthetwomajorcirculatorysystemstogetherwiththebloodvascularsystem.Thisnewly discoveredlymphaticsystemwasfurtherconfirmedbyHerophilus (335–280BC)andErasistratus(304–250BC)throughsystematic dissectionsofhumancadavers [3,4].However,suchhistorical discoverywaslargelyignoreduntilGasparoAsellirediscovered thesystemin1627,describingmesenterylymphaticvesselsin caninesasthe“venaealbaeetlacteae (milkyveins)” [5]
Additionally,criticalstructuralcomponentssuchasthecollecting lymphaticvesselsandthethoracicductwerealsoidentifiedforthe firsttimeasadditionalanatomicalstructuresinthelymphaticsystem.However,thissystemhasbeenlargelyneglectedforthree
centuries,dueprimarilytolimitedknowledgeaboutitstruevalue andthetechnicaldifficultiesinvolvedinidentifyingitscomponent parts.Thus,thelymphaticsystemhasbeenconsideredlessimportantandtheoften-invisibleauxiliarytothebloodvascularsystem. Untilrecentyears,thelymphaticsystemhasbeenlargelyignored, whilethebloodvascularsystemhasbeenextensivelystudied, despitebothsystemssharingsomanyfunctional,structural,and anatomicalsimilarities.Forexample,theembryonicoriginofthe lymphaticsystemwasinitiallyinvestigatedmorethanacentury ago [6],butitonlyattractedproperscientificattentionduringthe eraofmolecularbiologyinthelastdecade,withtheresultthat themechanismsofmammalianlymphaticdevelopmenthavefinally becomebetterunderstood [7–9].Indeed,advancedexperimental modelstostudyvariousaspectsoflymphaticbiology,both invitroandinvivo,facilitatedtremendousprogressintheresearch intothedevelopmentandfunctionofthelymphaticsystem; togetherwithvariousnewlydiscoveredmolecularmarkerstodistinguishbetweenbloodandlymphaticvessels,thisresearchchangedthemisconceptionofthelymphaticsystemassecondaryto themoreessentialbloodvascularsystemforthefirsttimeintwo decades.
Recentadvancesinourunderstandingoftheembryonicdevelopmentofthelymphaticvasculatureincludethemolecularmechanismsmediatinglymphangiogenesisandtheroleof lymphangiogenesisinchronicinflammationandlymphogenous cancermetastasis [10].Indeed,thegrowingevidenceabouthow thelymphaticsystemcontributestovariousinflammatorydisorders andlymphedemaaswellascancermetastasishasboostedbasic lymphaticresearchonthissecondvascularsysteminhighervertebratesbeyonditsbasicfunctionintheabsorptionofdietaryfatinthe intestine,immunesurveillance,andtheregulationoftissue pressure.
Ontogenicpointofview
Likeallvascularstructures,thelymphaticconduitsarisefrom endothelialcellaggregatestobecomeanintegralelementofthe mammaliancirculationthroughthecoordinatedprocessof
lymphvasculogenesisandlymphangiogenesis(Fig.1).Differenttheorieshavebeenproposedabouttheoriginofthelymphaticsystem, andithasremainedacontroversialissuesincetheearly20thcentury.Therearetwocompetingtheories,the“centrifugal”andthe “centripetal”models,andsomeareasofcontentionremainunresolved [11–18].
The“centrifugal”modelisbasedonthehypothesisthatthelymphaticsystemisderivedfromthebloodvascularsystemduringits earlydevelopment,whilethe“centripetal”modelclaimsthat
FIG.1 Step-by-stepdevelopmentofthemammalianembryoniclymphaticvasculature. Developmentofthelymphaticsiscomposedoftwosteps:lymphangiogenesisandlymphvasculogenesis.Someofthecardinalveinendothelialcellscommittothelymphaticlineage(secondleft).Theprimitivelymphsacisformedbybuddingoffthevein(bottomleft). Lymphaticendothelialcellssproutandmigratefromthelymphsactoformthelymphatic vascularnetwork(right).
mesenchymalcell-derivedlymphangioblastsformtheprimitive lymphaticplexusesfirstbeforeestablishingtheconnectionstothe embryonicvein.The“centrifugal”modelexplainsthattheprimary lymphsacsarisefromtheendothelialcellpopulationoftheembryonicveinsearlyinfetaldevelopmentandthatisolatedprimitive lymphsacsthencontinuetoprogressthrough“endothelial sprouting”tospreadasperipherallymphaticvesselsintothesurroundingtissuesandorganswherelocallymphaticcapillariesform.
Inthehumanembryo,thelymphaticvesselsappearat6–7weeks, substantiallylaterthanthebloodvascularstructures [11] andnearly 1monthaftertheappearanceofthefirstbloodvessels [12].The pairedstructuresofjugularlymphsacsadjacenttothejugularsectionofthecardinalveinaretheearliestidentifiableprecursorsof embryoniclymphatics.However,theoriginoftheselymphsacs andtheirrelationshiptotheadjacentcardinalveinhaveremained controversialuntilrecently [10,13].AlthoughSabinFRdemonstratedwithexperimentsoninkinjectionintotheveinsofpig embryosthatthelymphaticsystemisderivedfromtheearlyembryonicvein [14,15],thepresenceoflymphangioblastsaslymphatic progenitorcellsandthecriticalroletheyplayhavealsobeenvalidatedinembryonicdevelopmentofthenonmammalianlymphatic system [16–18].
Incontrast,the“centripetal”modelexplainstheprocessindependentlyoftheveins,postulatingthatthelymphsacsaredeveloped fromlymphangioblasts,themesenchymalprecursorcells [19,20]. HuntingtonandMcClureetal. [20] claimedthattheprimitivelymphaticvesselsariseindependentlyfromthelymphangioblastsinthe mesenchymewithnoconnectiontotheveinsuntiltheyfusewiththe lymphsacsthroughcentripetalgrowthtoestablishvenousconnectionsasasecondaryprocess.Thistheorywasfurthersupportedby thefindingsofexperimentalworkinthequail-chickchimerasystem onlymphangioblastsintheavianwingbudbeforetheemergence ofthejugulo-axillarylymphsacs [21,22].Thedistalwingbudsof 3.5-day-oldchickembryosweregraftedintothesameplacein 3–3.5-day-oldquailembryostodeterminetheoriginofthelymphaticendothelium.Thevascularendothelialgrowthfactor receptor-3(VEGFR-3)andQH1doublestainingofthe10-old-day chimericwingsrevealedthatlymphaticswereformedfromboth chickandquailendothelialcells [22].Thisworkshowsthattheearly
lymphsacsappeartoariseassproutsfromadjacentveins,whileat thesametime,mesenchymallymphangioblastsalsogrowtoward thoselymphsacs.
Thereismuchevidencetosupportbothcentrifugalandcentripetaltheories,butthecentrifugalmodelappearstomorecloselymirrortheprocessinhighermammals.ThestudiesinProx1-deficient micegavecrucialsupporttoSabin’scentrifugalmodel [23,24] and havesubsequentlybeenconfirmedbyothers [25,26].However,mesenchymalcellsexpressingCD31andCD45alongwithlymphatic endothelialmarkers(Prox1andLYVE-1)observedinmouse embryossuggestthatthesecellsmightserveaslymphendothelial precursors [27].Thisgivesongoingsupporttothecentripetal hypothesis [17,28],particularlyinthetissue-specificbrain,cardiac, intestinal,visceral,anddermallymphatics [9],despitethefact thatSabin’sclaimsthatlymphaticendothelialcellsareexclusively derivedfromtheendotheliumofthevenoussystemhasbeen themostwidelyacceptedhistorically,withfurthersupportby Wigleetal. [14,15,24].
Phylogeneticpointofview
Thecardiovascularcirculatorysystemofbloodvesselsandthe heartdevelopsmuchearlierthanthelinearconduitsystemofthe lymphaticvessels.However,thereissomeevidencethatthisfirst vascularsystemincludedsomelymphaticfunctionstoprovideall livingorganismswithcrucialdefensemechanismsirrespectiveof theirsize [29].Forexample,macrophagesappearfirstinthecirculationofthelympho-hematicsystemininsectsbeforeerythrocytes develop,demonstratingthatlymphaticfunctionisprimary.
Indeed,theearlybloodvesselsinvertebrateshavesomestructural characteristicsoflymphaticsinthattheyexpressthelymphendothelialreceptorflt-4,whichrepresentsVEGFR-3.Thisuniquecharacteristicremainsuntilthedefinitivelymphaticsdeveloplater,atwhichtime flt-4isrestrictedtothosestructuresalone,whichareformedeither frommesodermallymphangioblastsorfromtheprimaryvessels [29].
Inaddition,theheartisnottheonlyorgantopumpcellsforcirculation.“Lymphhearts”arepresentinlowervertebratesandalso developinsomebirdstransiently.Eveninhumanbeings,thereisa
vestigialformofthecontractilesystemforthelymphaticcirculation, definedasthe“lymphangion,”whichcirculatesimmunecells. Hence,thebloodvascularsysteminmammalscandevelopfrom theprimitivelymphaticsystemoflymphheartsbeforethedefinitive lymphaticsdevelop.
Lymphaticvesselsindependentofthebloodvascularsystemare identifiedfirstlyincartilaginousfish.Inbonyfish,arteriesandveins areconnectedbybloodcapillariesandformaclosedbloodvascular systemandarecompletelyseparatefromthelymphatics [30]. Recently,aprimitivelymphaticsystemwasdiscoveredinzebrafish [26,31] thatdemonstratesevolutionarilypreservedstructuraland cellularfeaturesandhasbecomeextremelyvaluableinvarious geneticstudies.
Thelymphaticvesselsarewelldevelopedintailedamphibians suchassalamandersandnewts.Inamphibianswithouttailssuch asfrogsandtoads,thesuperficiallymphaticsfuseduringmetamorphosistoformlargesubcutaneouslymphsacsintheadultanimals [30,32].Amphibians,reptiles,andflightlessbirdshavedevelopeda specializedlymphheartforlymphdrainageandtransportthrough thelymphaticsystem(Fig.2).However,thelymphaticsystemof
FIG.2 Schematicdiagramillustratingthelymphaticsandlymphhearts (arrows) in salamander,frog,andavianembryos.Salamandershavepairsoflymphheartslocated segmentallyoneachsideofthelaterallymphduct.Frogshaveapairofanteriorandposteriorlymphhearts.Avianembryostemporarilydevelopposteriorlymphhearts. Basedon KotaniM.Thelymphaticsandlymphoreticulartissuesinrelationtotheactionofsexhormones. ArchHistolCytol1990;53:1–76.
flyingbirdsandmammalslostthelymphheartthroughthefurther evolutionofthelymphaticsystemandacquiredlymphnodesfor immunefunctionsinstead.Avianandreptilianlymphaticsonly differfrommammalsinthatthejugularlymphsacinmammalsis morehighlydevelopedasananterior/cervicalveno-lymphatic heart [26,27].Therefore,thelymphaticsystemisbelievedtohave appearedfirstinvertebrates [33] asanessentialcomponentofthe immunesystemandtomaintainfluidhomeostasiswithinthebody.
Vasculogeneticpointofview
Throughthelate1990s,theidentificationoflymphaticendothelial cell(LEC)-specificVEGFR-3 [34] gavemomentumtothestudyof lymphvasculogenesisstudyusinglymphatic-specificmolecular andcellularmarkers.AlthoughVEGFR-3expressionisdetectable inamajorityofvascularendothelialcellsduringearlydevelopment, VEGFR-3isthefirstlymphatic-specificmarkerrestrictedtolymphaticplexusesatlaterstagesofdevelopmentandpostdevelopment [34].VEGF-C(aligandforVEGFR-3)-deficientmiceare unabletoformrudimentarylymphaticvesselseventhoughthe endothelialcellsremaincommittedtothelymphaticlineage.This mutantphenotypecanberescuedbyVEGF-CandVEGF-D,another VEGFR-3ligandshowingVEGFR-3specificity [35].
Thetremendousincreaseinknowledgeoflymphaticdevelopmentatthemolecularleveloverthelasttwodecadesallowed lymphvasculogenesistoberedefinedaccordingtonewlydiscoveredtissuemarkers.Lymphvasculogenesisisnowfurtherverified throughfourdistinctivelydifferentstages:lymphaticcompetence, commitment,specification,andvascularcoalescenceand maturation [13]
Lymphatic/LECcompetence torespondtotheinitialinductionsignalsforlymphaticvasculardifferentiation [36] isrepresentedbythe cellularexpressionof flt-4 genethatencodesforVEGFR-3 [10] togetherwithlymphaticvesselendothelialhyaluronanreceptor-1 (LYVE1) [19,37].TheyrepresentcrucialmolecularsignalingpathwaystoprimeLECstoinitiatelymphaticdevelopment [38,39]. Forexample,mouseembryosthatlackVEGFR-3expressiondie withoutlymphaticdevelopment.VEGF-C/VEGFR-3signalingalso
12 2.Ontogenyandphylogenyoflymphatics:Embryologicalaspect
playsakeyroleacrossmultiplestagesoflymphaticvasculardevelopmentbecauseVEGF-CbindingtoVEGFR-3transducessignals thatpromotelymphaticendothelialcellsurvival,proliferation, andmigration [40,41] sothatmouseembryosthatlackVEGF-C donotdeveloplymphsacs [42].
Lymphaticcommitment isrepresentedbytheexpressionofProx1, whichhasacentralroleinexplainingthecentrifugalmechanismthat isahomologoftheDrosophilahomeoboxtranscriptionfactorprospero7andservesasamasterregulatoroflymphaticdevelopment. Prox1expressionistheexclusivenucleartranscriptiontocellsofcommittedlymphaticlineage [19].Thisexpressionrepresentsaclear-cut shiftincommitmentofthevenousendothelialcellstoalymphaticlineage [20].TheexpressionofProx1withintheembryonicendothelial cellissufficientforlymphaticcommitment.Prox1-positivelymphatic endothelialcellssubsequentlybudandmigrateawayfromtheveins [9] toformaninitiallymphaticplexusandfurtherdevelopthelymph sacs [43–45].However,theinitiationofProx1expressioninvenous endothelialcellsisdependentonthetranscriptionfactorsSox18 [46] andNr2f2/Coup-TFII [47] inmammals [9].Prox1isahomolog oftheDrosophilahomeoboxtranscriptionfactorprospero7and servesasamasterregulatoroflymphaticdevelopment.
Lymphaticendothelialcellspecification involvesthemandatory expressionofthemolecularmarkersofLECidentitythatleadto theuniquelymphaticendothelialphenotype.TheseincludepodoplaninandVEGFR-3andneuropilin2 [43–46].Whenthenewly developingLECsleavetheveins,thelymphaticcellpopulation establishescompleteautonomyinthevenousmicroenvironment throughtheseuniquedevelopmentalsteps.Peripheralmigration occurs,andbuddingandmigrationprecedetheformationofprimarylymphsacs.Thecellsformcapillariesinacentrifugalfashion, establishingthelymphaticvasculature [10]
Vascularcoalescenceandmaturation. Theembryonicperipheral lymphaticvasculaturegoesthroughtheprocessofsubstantialmaturationandremodeling,includingthedevelopmentofvalveapparatus.FOXC2,whichishighlyexpressedinadultlymphaticvalves, specifiesacollectinglymphaticvesselphenotype [48,49].Valve developmentisalsodependentonGATA2 [50].Selectiveknockout ofGATA2inthemurinelymphaticendotheliumleadstomajor defectsinvalvestructureandcausesdistendedcollectinglymphatic
vessels.BMP [51],Notch [52],andsemaphorin3a-neuropilin-1 [53] arealsoknowntoplayanimportantroleinvalvulardevelopment asadditionalsignalingpathways.
Theephrinsandtheangiopoietinsalsocontributetolymphatic vascularmaturation.FaultyexpressionofephrinB2wouldresult inhyperplasiaofthecollectinglymphaticsandabsentvalveformation [54].EphB4alsohasaroleinsignalinginlymphaticvesselvalve development [55].Angiopoietin1and2(Ang1andAng2)alsoparticipateinthematurationofthelymphaticvasculature [56–58].All ofthesedevelopmentaleventsareinterrelatedandcomplex.New molecularparticipantsintheprocesscontinuetobeidentified.
Conclusion
Even400yearsaftertherediscoveryofthelymphaticsystemby GasparoAselli,thelymphaticsystemremainedmisunderstoodas asecondaryvascularsystemtosupportthebloodvascularsystem. However,thishasnowchanged.Ourunderstandingofthelymphaticsystemhassignificantlyadvancedoverthelasttwodecades, withmanylandmarkdiscoveriesinlymphaticresearch,especially intheareasofcellularandmolecularbiologyofLECs.Thesenew discoverieshavebroughttolightthemolecularcontrolofphysiologicalandpathologicallymphangiogenesisandsubsequentlychangedtheparadigmtore-evaluatethelymphaticsystem’sessential roleinthehumancirculatorysysteminabrandnewway.
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Furtherreading
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