Cajal间质细胞100年史.docx

Cajal间质细胞100年史.docx

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Cajal间质细胞100年史

OneHundredYearsofInterstitialCellsofCajal

LARSTHUNEBERG*

InstituteofMedicalAnatomy,UniversityofCopenhagen,DK-2200Copenhagen,Denmark

KEYWORDShistory;microscopy;gastrointestinaltract;smoothmuscle;pacemakercells;myoidcells

ABSTRACTThisreviewisaportrayaloftheevolutionofideasinvolvingtheinterstitialcellsofCajalinchangingdisguisesasdullfibroblasts,notveryexcitingSchwanncells,orperhapsquiteimportant,thoughprimitiveneurons.However,todayunmasked（webelieve）,theyrevealthemselvesasmyoidcells,arolethat,judgingbycurrentinterest,isfarmoreexcitingthanformerones.

Closeto500publicationsfrom1860-1999havecontributedtothediscussioninonewayortheother.Thisliteraturecontainsawealthofcorrectobservationsbutobviouslyalsowronginterpretations,whichareseenasaresultoftooblindabeliefinspecificitiesofvisualizationmethods,combinedwithadesiretointerpreteventhehiddendetail.

Ithasbeenmyobjectivetoattempttotracetheoriginsofviableideas,andIhavethereforefocusedonrelativelyfewauthors.Themostrecentdevelopmentfrom1980untiltodayissowellcoveredbyeasilyaccessiblereviewsthatIhaveresortedtoamere,buthopefullycomplete,listofthem.

ModernICC'istshavesofarbeencaughtintheexternalmuscleofthegutandkepttheirhandsoffitsinternalaffairs.However,whileworkingmywaythroughtheliteratureitstruckmethatanumberofrecentstudiesmayprovidetheelementsofaplausiblemodelforthevillouscontractionmechanism.Inthepresentcontext,animportantpointisthattheveryfirstpublishedinterstitial“neurons”fromCajal'shand--oftheintestinalvillus,1889--mayachievenewsignificanceasapossiblecorrelatetotheregulatoryICCoftheintestinalmuscularis.Partlytomakethispoint,Ihavetakenthelibertyofgivingashortaccountofrecentresultsfromourlab.Microsc.Res.Tech.47:

223-238,1999.©1999Wiley-Liss,Inc.

INTRODUCTION

ThestoryoftheInterstitialCellsofCajalisthefascinatingtaleofchangingconcepts,asemergingthroughtheinterferencebetweenunlimitedscientificintuitionanditsformalrestraintsbydevelopingbutalwayslimitedmethodology.Itisthisinterplaythatliesbehindtheevolutionoffundamental--andfundamentallycorrect---conceptsmanydecadesbeforethemethodsadvancedtothestageofprovidingsolidevidence,ifnotproof.

Thus,thegreatSpanishneuroanatomist,SantiagoRam6nyCajal,throughstudiesofthesecellsarrivedatthehypothesis（1911,p.928）thatnetworksofanastomosing1interstitialcellswereinfluencedby“principal”componentsofthenervoussystem,whiletheinterstitialcells（seenas“accessory,”primitiveneurons）exerteddirectregulatoryeffectsonsmoothmusclecontraction.Quiteindependently,thediscovererofthecardiacsino-atrialpacemakerorganization,SirArthur

*Correspondenceto:

LarsThuneberg,InstituteofMedicalAnatomy,SectionC,ThePanumBuilding,3,Blegdamsvej,DK-2200CopenhagenN,Denmark.E-mail:

L.Thuneberg@mai.ku.dk

1Today:

cellswithoverlappingprocessescoupledbygapjunctions.

Keith（1914,1915）,apparentlynotevenawareofthefactthathewasreferringtothe“cellsofCajal,”suggested（fromscantyevidence）thatthesecellsconstitutedapacemakersystemoftheintestinalmusclelayers.Thetechniquesnecessarytoproveordisprovetheseideaswerenotdevelopeduntil7-8decadeslater.Asithappenedbothwereprovenessentiallycorrect.

Itisactuallywellover100yearssincethefirstdescriptionsofthecellsthatwe—withthefamousRussianhistologistAlexanderS.Dogiel2—knowastheinterstitialcellsofCajal3（ICC）.ThegraphsinFig.1arebasedonthereferencesgiveninmyearlierreview（Thuneberg,1982;table1）,supplementedwiththecompiledreferencesfromthe1980sand1990sasextractedfromtwolaterreviews:

Thunebergetal.（1995）,andFaussone-PellegriniandThuneberg（1999）.

AglanceatthegraphssuggestsfourperiodsoflivelyinterestintheICCwithrelativelowsinbetween.However,thefirstandseconddeclinesinthenumberofpaperscovertheyearsofthetwoWorldWars,andareatleastpartiallyexplainedbywartimelimitstobasicscientificworkandcommunication.

Sothisleavesfiveperiods:

（1）theearlyyearsbefore1889;

（2）1889-1925;（3）1925-1960;（4）1960-1980;and（5）1980totoday,theboundariesnottobetakentooliterally.

THEPERIODBEFORE1889:

WHOSAWTHEICCFIRST?

Anillustration（Fig.2）ofanintestinalvillusfromthedissertationbyWiegandt,asearlyas1860,showsconnectivetissuecells（Bindegewebskörperchen）,whichmaybeanearlyversionoftheinterstitialneuroneslaterdescribedbyCajal（1889）inthesamelocation（Fig.4A）.Judgingfromthedrawingsoftheintravillousnerveplexus,firstdescribedbyDrasch（1880）（Fig.3）,CajalandDraschillustratedtwodifferentstructuresincontrasttomostlatercitations（seeFig.4B:

intravillousnerves;fromCajal,1911）.ThereislittledoubtthatsomeofthecellsthatCajaldescribed,inparticularinterstitialcellsofintestinalvilli,wereamongthoseobservedanddiscussedincontemporaryhistologytexts（His,Henle,vonKölliker）.Ofthese,vonKölliker'sHandbuchderGewebelehredesMenchen（1867,1896）wasamajorcontemporaryreferenceworkandmaintainedtheviewthatthecellsinquestionwereconnectivetissuecells.

ItispossiblethattheICClocatedbetweenthemusclelayersoftheexternalintestinalmusculaturethatCajalandhisstudentsdemonstratedinthe1890s,werethoseillustratedearlierbyGerlach（1873）.

THEPERIOD1889-1925:

GOLGI,CAJAL,DOGIEL,ANDKEITH

In1889,Cajalpublishedthefirstshortpaperontheinterstitialcelltypethatcametobeassociatedwithhisname.Inthispaper,theGolgimethod（silverimpregnation）isappliedtointestinaltissuefromguinea-pigandrat.Thisdrawingof“multipolar,anastomosingnervecells”invilliisreproducedinFigure4A.WhywouldIincludeaclaimthatanetworkofneuronsshouldexistinalocation,whereweknowtodaythatneuronsarenotpresent?

Myrealreasonwill

2DieZellenRamónyCajal’s’,asearlyas1895.

3ReferencetotheSpanishanatomistareinsomejournalslistedas‘RamonyCajal,S.’,althoughmoreoftenas‘Cajal,S.R.’.Hildebrand（1989）citesacommentfromtheSwedishanatomist,GustafRetzius,whohadaskedRamónyCajalaboutthecorrectcitationandquotesthereplyfromhim:

“ForseveralreasonsthenameCAJAListoprefer:

RÁMONisaverycommonname,andisalsousedasaChristianname”.AndheaddsthatRamónyCajalofteninhisownwritingsusestheshortform,Cajal.

becomeobviouslater（seePerspectivesforFutureResearch）.Inthehistoricalcontext,1889wastheyearwhenCajalpresentedhisresultsobtainedwiththeGolgistaintotheforumoftheworld’sleadinganatomistsatthe3rdmeetingoftheGermanAnatomischenGesellschaftinBerlin.Cajal’sresultsstronglysupportedtheneurontheory（usuallyascribedtoWaldeyer,2yearslater）:

thatthenervoussystemismadeupofindividualcellsformingpolarizedcontacts,synapses（thewordcoinedbySherrington,10yearslater）.Opposedtothe“neuronists”werethe“reticularists”whoheldthatthenervoussystemwasorganized,notasanassemblyofindividualcells,butasatruesyncytium,anervenet.InCajal’sRecollectionsofMyLife（1901-1917;Englishtranslation,1937,p.356）hequotesaBelgianneurologist,vanGehuchten,whoparticipatedinthemeeting:

“Thedistrustwassuchthat……Cajal,whoafterwardsbecamethegreathistologistofMadrid,foundhimselfalone,excitingaroundhimonlysmilesofincredulity.”However,thegrandoldmanofhistology,vonKo11iker,then72yearsold,wastakenasidebyCajal,wasshownhismicroscopyslides,andbecamesoconvincedthatCajalwasrightthathefromthenonbecamehissupremesupporter.ItspeaksofvonKölliker’sopenmindthathesupportedhis“reticularist”friend,"ilgrandeCamilloGolgi,"equally,rightuptohissharingthe1906NobelprizewithCajal（seeHildebrand,1989,foravividdescriptionoftherelationsbetweenthesethreescientists,andfullreferences）.

ThereissomeironyinthefactthatCajalobservedanddescribedperipheralcellorganizations--theICC--whichseemedtoviolatetheneurondoctrineforwhichhewastheforemostdefender.Thatheatthesametimewas--andremained--anopen-mindedinvestigatorisapparentfromtheconcludingcommentsinhisposthumouspublicationfrom1934（inFrench）:

“Iamneithernarrow-mindednordogmatic.Itakeprideinpreservingamentalflexibilitywhichdoesnotfearcorrection.Theneuronaldiscontinuity,veryevidentinnumerousexamples,mightbesubjecttoexceptions.Ihavemyselfreportedsomeexceptions,e.g.,thosethatprobablyexistintheglands,thebloodvessels,andtheintestine（myinterstitialneurons）.”

OutofthethreelocationstowhichCajalrefers,itistheICClocatedintheintestinalmuscularisexternathatarethesubjectofcurrentlyboominginterest.Thesecellsweredescribedbyhimin1892,1893,and1894（Figs.5and6）.Cajal’supheld,buterroneous,beliefthatthecellsinquestionwereneurons,wasduetothefactthatthe—multipolar—cellsbecamepositivelystainedbytheGolgimethod（Figs.4A,4B,6）andEhrlich’svitalmethylenebluemethod（Fig.5）,bothofwhichinhisownhandsandexperienceweresuperiortoolsforthestainingofneurons.Apartfromv.Kölliker,theforemostdissidentwasDogiel（1895,1899）whostressedtheperivascularlocalizationofCajal’scellsanddeclaredthatitwasfullyjustifiedtoclassifythemasconnectivetissuecells.ThatDogielandCajaldidobservethesamecellsisevidentwhenFigure7（Dogiel）iscompar