[PDF] The senescence-associated secretory phenotype induces

The senescence-associated secretory phenotype induces

Jan 31, 2017 · Génétique et de Biologie Moléculaire et Cellulaire, UMR7104, Centre National de la Recherche Scientifique, U964, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch 67404, France Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes However, while

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The senescence-associatedsecretory

phenotype inducescellular plasticity and tissuer egeneration

Birgit Ritschka,

1,2

Mekayla Storer,

1,2,9

AlbaMas,

1,2

Florian Heinzmann,

3,4

Mari CarmenOrtells,

1,2

Jennifer P.Morton,

5,6

Owen J.Sansom,

5,6

Lars Zender,

3,4,7 and WilliamM. Keyes 1,2,8 1

CentreforGenomic Regula tion(CRG), TheBarcelonaInstituteof Scienceand Technology ,Barcelona08003, Spain;

2

Universitat

PompeuFab ra(UPF),Barcelona 08003,Spain;

3 Departmentof InternalMedicine VIII,Univ ersityHospital Tübingen,72076

Tübingen, Germany;

4

Departmentof Physiology I,Instituteof Physiology ,EberhardKarls University Tübingen,72076Tübingen,

Germany;

5 Cancer ResearchUKBeatson Institute, GlasgowG611BD, UnitedKingdom; 6

Instituteof CancerSciences, University

of Glasgow,GlasgowG61 1BD,UnitedKingdom; 7 TranslationalGastroi ntestinalOncologyGroup,GermanConsortium for TranslationalCancerResearc h(DKTK), GermanCancerResearchC enter(DKFZ), Heidelberg69120, Germany; 8

Institutde

Génétiqueet deBiologie Moléculaire etCe llulaire,UMR7104, Centr eNationaldelaReche rcheScientifique, U964,Institut

Nationalde laSanté etde laReche rche Médicale, Université deStrasbourg,Illkirch67404, France

Senescence isa formof cellcycle arrest inducedby stress suchasDNAdamage andoncogenes. Howe ver,while

arrested,senescentcells secretea varietyof proteins collectively known asthe senescence-associatedsecretory

phenotype (SASP),which canreinfor cethe arrestandinduce senescencein aparacrine manner.Ho wever, theSASP

has alsobeen shown tofavorembryon icdeve lopment,woundhealing,and eventumorgro wth,suggestingmore complexphy siologicalrolesthan currentlyunderstood. Here weuncovertimely newfunctionsofthe SASPin

promotinga proregen erativeresponsethroughtheinductionof cellplasticityand stemness.Wesho wtha tprimary

mouse keratinocytestransientlyex posedtotheSASP exhibitincreased expressi onof stemcell markersandr e-

generativecapacity invivo.How ever, prolongedexposure totheSASPcausesasubsequent cell-intrinsicsenescence

arrestto counterthe continuedr egenerative stimuli. Finally,byinducingsenescencein singlecellsinvivo inthe

liver,we demonstra tethatthisactivates tissue-specificex pression ofstemcellmarkers. Together, thisworkun-

coversaprimary andbeneficial rolefor theSASP inpromot ingcell plasticity andtissue regenera tionand introduces

the concepttha ttransientthera peuticdeliveryof senescentcellscouldbe harnessedtodrivetissue regenera tion.

[Keywords: senescence;plasti city;stemcells; papilloma;CD34;SASP]

Supplemental materialisav ailablefor thisarticle.

ReceivedSeptember13, 2016;revis edve rsiona cceptedJanuary4,2017. Cellularsenescence canbe inducedby avariety ofs tress stimuli.These caninclude active oncogenesignaling, DNA damage,irr adiation,orchemotherapy ,causing the activationoftumor suppressor networks,including p53, ranoet al.1997; Schmittet al.2002; Coppe etal. 2008; Campisi 2013).Ther eby,senescenceacts asa cell-intrin- sic tumor-suppressivemechanismthatpre vents thepro- liferationof damagedcells. Howe ver,senescence can also contributeto tumorsuppre ssionin acell-extrinsic manner throughsenescence-associated secretorypheno- type (SASP)-mediatedrecruitment ofimmunecells (Kang etal. 2011;Lujambio etal. 2013).Cellularsenescence isalso inducedupon replicative ag- ing ofcells inculture ,and senescentcellsaccumula tein multiple tissuesand stem cellsduringphysiological aging nonproliferatingcellscontributes tothe lossof functional and regenerativecapacityinaged tissues,preventingpro- liferationof bothsomatic ands temcells ina cell-intrinsic manner (Janzenet al.2006; Krishnamurthyet al.2006; Molofsky etal. 2006;Sharpless andDePinho 2007;Sou- sa-Victor etal. 2014;Bak eret al.2016;Garcia-Pr atet al.

2016). Additionally,senescentcells cancontribute to

loss oftissue functionduring agingthrough non-cell-au- tonomous mechanisms.This canres ultfr omSASPpro- teins disruptinghomeos tasisorpossiblythr oughthe induction ofpar acrinesenescenceinneighboringcells 9 Present address:Programin Neurosciences andMen talHealth,Hospital for SickChildren, Toronto, OntarioM5G0A4, Canada.

Correspondingauthor:bill.ke yes@igbmc.fr

Article isonline athttp:/ /www.genesdev.org/cgi/doi/10. 1101/gad.290635.

116. Freelyavailable onlinethrough theGenes&DevelopmentOpen Ac-

cess option.© 2017Ritschka etal. Thisarticle, published inGenes&Development, is availableunder aCrea tiveCommons License(Attribution-NonCom- mercial 4.0Intern ational),asdescribedathttp:/ /creativecommons.org/ licenses/by-nc/4.0/.

GENES&DEVELOPMENT31:1-12 PublishedbyCold SpringHarbor LaboratoryPress; ISSN0890 -9369/17;www.genesdev.org 1

Cold Spring Harbor Laboratory Press on June 16, 2023 - Published by genesdev.cshlp.orgDownloaded from

(Bakeret al.2011; Acosta etal. 2013;Campisi2013). Therefore,thissupports how agingand decreasedregener- ation mayinpart resultfro msenescence andtumor-sup- pressivemechanisms. Recently,howev er,beneficialrolesforsenescence have been emerging,often mediated throughtheSASP .Inthe developingembryo ,senescentcellsare suggested tocon- tribute totissue development andpatterningthroug h both remodelingmediated bysenescentcellclear ance and tissuegro wthandpatterning through theSASP(Mu- noz-Espin etal. 2013;Store ret al.2013).Inaddition, sen- escent cellsrecruit immunecells andlimit fibrosis during wound healingand contributeto woundr epairthrough the secretionofgro wthfac tors(Krizhanovskyet al.

2008; Junand Lau2010; Demariaet al.2014). Howev er,

ing canhav eunwantedside effectsthroughpromoting tu- mor growthandprogr ession(Krtolica etal.2001;

Yoshimotoet al.2013).

Reconcilingthese beneficialand detrimentalaspects

of thesenescence program hasbeendifficult.Her e,we describe howtransient exposuretothe SASPcanpromote a subsequentcell-intrinsic arrest, likelyasa tumor-sup- pressiveres ponsetoaberrant regenera tion.Thisworkun- coversimportantmechanis ticinsights intothebiological function ofsenescence.

Results

Toex plorethesenescenceprogr amin epithelialcells, we performed microarrayanalysison primarymousekerati- nocytes undergoingoncogene-induced senescence(OIS) fromthe expression ofoncogenicHRas V12 . Asex pected, senescent keratinocytesexhibitedhallmarkfea tures of senescence, includingdecrease dproliferation, alargeflat appearance,incre asedsenescence-associated-galactosi- dase (SA--Gal)a ctivity,andincreasede xpression ofp53, p21, andp16 (Supplemental Fig.1a -d). Analysisofthe mi- croarraysignaturerevealedthatotherknownmediators of senescence andthe SASPw erealso increased,including p15 (Cdkn2b), Il1a,and Hmga2(Fig. 1A).Surprisingly , however,senescentcells alsoe xhibitedincreased expres- sion ofmany genesnormally associated withsomatic and cancerste mcells,includingCD34, Lgr6,Pr om1, CD44, Ngfr,and Nestin(Fig. 1A).This was furthersup- ported bybioinforma ticsandgeneset enrichmentanaly- sis (GSEA)using Genomatix softwareandpublished signaturesof commonste mcell populations(Fig.1B,C; for fullgene lists, seeSupplemental Table1; Blanpain et al.2004). To validatethissigna ture,weperformed quantitativePCR (qPCR)analys isfor selectedskinstem cell genesin senescentcells upto 2wk after infection (Fig. 1D).As before, wefoundincreasede xpression of many ofthese, includingCD34, Nestin, Lrig1,and Lgr6 as wellasother hairfollicle stem cell(HFSC) genes (Supplemental Fig.1f ). Similarobservatio nswerealso no- ticed inthe primarycontrol cells,which undergosenes- cence-likechanges uponpro longedculture ,includingadopting asenescent-lik emorphologyande xhibiting increasedex pressionofp16(Supplemental Fig.1e,h ). Surprisingly,these cellsalso displaye dan increaseinthe same stemcellgenes, althoughat lower levels than seeninOIS (Supplemental Fig.1e,g ). Supportingtheunan- ticipatedlink between senescenceandstemness, when senescence wasinducedin additionalwa ys, including treatmentofcells withthe chemotherapeutic drugetopo- side orirra diation,thecellsalso displayed anincre asein the sameste mcellgeneswhile undergoingsenescence (Fig. 1E-F). Furthermore,in agreementwith thetrans criptpro file, upon OISinduction, wefound asignificant increase in the numberof newborn keratinocytesthat weredouble- positivefor CD34and integrin-6 proteins,whichlabel a distinctpopulation ofHFSCs(Fig.2A; Supplemental

Fig. 2a

;Blanpainet al.2004; Jensenet al.2010). Interest- ingly,ne wbornkeratinocytes donotyetexpress these stemcell markers, whichbecomeexpresse dafte rest ab- lishment ofthe haircycle inthe adult,suggest ingthat these markersare beinginduced deno voduring senes- cence induction( Supplemental Fig.2b -d). Remarkably, however,ev enthoughtherewa san increase instem- ness-associatedmark ers,thesecellswer estil lundergoing proliferativearrest, asmeasuredby aprogr essivedecrease in proliferation(Supplemental Fig.1c )anda lossof clono- genic capacityinthe total(Fig. 2B,C)and double-positive CD34/integrin-6 cells(Fig. 2D;Supplemental Fig.2e ).In- deed, qPCRanalys isonthedouble-positiv eCD34/integ- rin-6 populationshowe dthatthesecellswere not escaping senescencebut expresse dhighlevelsofthesen- escence markersp16and p21(Fig. 2E;Supplemental Fig.

2f). Together,theseres ultsdemonst ratethatsenescent

cells, whileundergoing senescencearre stand lossofclo- nogenicity,parad oxicallyexhibitincre asedmarkersnor- mally associatedwithste mness.

Toinve stigatethisunexpectedconnection between

senescence andste mcellsinvivo, weex plored theinci- dence anddis tributionofsenescencein papillomasthat wereinducedwith DMBA/TPAtr eatment, anin vivo model ofOIS. Upone xaminationof establishedpapillo- mas forSA- -Gal activity,nosta iningwa sdetectablein the epitheliallay ersofthetumor, withthe strongest reac- tivity foundin theunderlying dermaltissue andsome re- gions ofthe papillomastr oma(Fig. 3A -H). However,a thoroughanaly sisoftheex pression patternsof known senescence markers—including p16,p21, p19,p53,

H2AX, andKi67 —by immunohistochemistrydemon-

stratedhigh express ionoftheseproteinsin theepithelial cells andthe underlyingdermis, witha more diffusee x- pressionin thes tromaof thebenignlesion(Fig. 3I-K,

Supplemental Fig.3a

-c). Papillomaarisesfro mthe aber- rantupward expansion anddifferentiation ofCD34 stemcells inthe basaland earlydiffere ntiating layers of the epithelialpapilloma (Fig.3L; Malanchiet al.2008; Lapouge etal. 2012).Detailed quantification ofthe distri- most highlye xpressedinthesesameste mcell layers (Fig. 3M;Supplemental Fig.3d ). Interestingly,thebasal- initiatinglay erofthepapilloma containedcells that

Ritschka etal.

2 GENES&DEVELOPMENT

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werepositive forbothprolifera tionmarkers (suchas Ki67 orPCNA) andsenescence markers, suggesting ady- namicprocessofaberr antpro liferationandsubsequent ar- rest( Supplemental Fig.3g -i). Giventhis result, we extendedour analysis toanothermodelof invivo OISin thepancreas,whereacti vationofmutantKRas G12D drives

senescence andpre malignantpancreaticintr aepithelialneoplasia (PanIN)lesions(Morton etal. 2010).Detailed

histologicalanalys isofthesetissues reveal edincre ased expressionofsenescence markers, includingSA- -Gal, p21, andp53, concomitantwith deceasedpro liferation (Supplemental Fig.4 ). Interestingly,herealso therewas increaseda ctivationofthestem cellmark ersCD44 and Nestinin thesesenescent lesions.Altogether, this V12 -inducedsen-

escent keratinocytescomparedwith growingkera tinocytes.Example genesareshown toillustratethat stem celland senescent genesare

morehighly expressed insenescentcells compared withgrowingcells. (B)Bioinforma ticsanalysisofgenessignificantl yup-regulated in

senescentcells (analysis performedusingGenom atixsoftware;full listof up-regulatedand down-regulated genesis inSupplemental

Table1 ). (C) GSEAof stem cellgenes(Blanpain etal. 2004)in thegeneexpres sionpr ofileof Ras-induced senescent kerati nocytes.(NES)

Normalizedenrichment score. (D) qPCRanaly sisforskinstem celland senescence genesin Ras-infected kera tinocytesat4-14 dpost- in-

fection(dpi)normaliz edtovector-infect edkeratinocytesat4dpi.n=4,ex ceptfor14dpi (n=3).( E) qPCRanalysisofetoposide-treate dker-

atinocytes3 -5 dafte rtreatment normalizedtoDMSO-treated keratinocytes3 dafte rtreatment.n=5,e xceptforday 5( n=3).( F) qPCR

analysisof irradiated keratinocytes(12 Gy)5and10daf terirr adiation normalized tok eratinocytes before irradiation.n=2.(D-F) Error

bars indicatemean± SEM.( )P<0.05;( )P<0.01;( )P<0.001),two-tail edStudent'st-test.

Senescence inducestissueregenera tion

GENES&DEVELOPMENT3

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demonstratesthat alsoinvivoin modelsof premalignant lesions, thereisa pronounced association ofstemcell markersin senescentcells.

Toinve stigatewhethercellsthat show increased ex-

pressionof stem cellmarkersin culture whileundergoing senescence mightbe escapersfrom thesenescence pro- gram orfunction ass temcells, weusedanin vivoassay to assessthe properties ofthesecells.T oaddre ssthis, in whichfr eshlyisolatedne wbornkeratinocytes orpuri- fied adultCD34

HFSCs aregr aftedalongwithdermal fi-

broblastsintofull-thickness woundsin theba ckof nude mice (Blanpainet al.2004; Jensenet al.2010). Thisr esults in largepa tchesofhairfollicles thatdeve lopdir ectlyfr om the transplantedcells( Supplemental Fig.5a ),whereas if the keratinocytesareplaced inculture priortotransplan- tation,they losetheir regenerativ ecapa city,generating only pigmentedscar tissue(

SupplementalFig.5b ). Wein-

vestigatedwhetherke ratinocytes expressingtheHRas V12 HRas V12 -infected keratinocytesundergoingsenescence.quotesdbs_dbs11.pdfusesText_17