Cell senescence contributes to tissue regeneration in zebrafish

Aging Cell. 2020;19:e13052.  
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1 o 5
h ps://doi.o g/10.1111/acel.13052
wileyonlinelib a y.com/jou nal/acel
Recei ed:4Ma ch2019
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Re ised:22July2019
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Accep ed:23Sep embe 2019
DOI: 10.1111/acel.13052
SHORT TAKE
Cell senescence con ibu es o issue egene a ion in zeb a ish
Sabela Da Sil a‐Ál a ez1 | Jo ge Gue a‐Va ela2,3 | Daniel Sob ido‐Cameán4 |
Ana Quelle2 | An ón Ba ei o‐Iglesias4 | Lau a Sánchez2 | Manuel Collado1
Thisisanopenaccessa icleunde  he e mso  heC ea i eCommonsA ibu ionLicense,whichpe mi suse,dis ibu ionand ep oduc ioninanymedium,
p o ided he o iginal wo k is p ope ly ci ed.
©2019TheAu ho s.Aging Cellpublishedby heAna omicalSocie yandJohnWiley&SonsL d.
1Labo a o iodeCélulasMad eenCánce y
En ejecimien o,Ins i u odeIn es igación
Sani a iadeSan iagodeCompos ela
(IDIS),Xe enciadeXes iónIn eg adade
San iago(XXIS/SERGAS),San iagode
Compos ela,Spain
2Depa amen odeZoología,Gené ica
yAn opologíaFísica,Facul adde
Ve e ina ia,Uni e sidadedeSan iagode
Compos ela,Lugo,Spain
3GeneaquaS.L,Lugo,Spain
4Depa men o Func ionalBiology,Facul yo 
Biology,CIBUS,Uni e sidadedeSan iagode
Compos ela,San iagodeCompos ela,Spain
Co espondence
ManuelCollado,Labo a o iodeCélulas
Mad eenCánce yEn ejecimien o,Ins i u o
deIn es igaciónSani a iadeSan iagode
Compos ela(IDIS),Xe enciadeXes ión
In eg adadeSan iago(XXIS/SERGAS),
San iagodeCompos ela,Spain.
Email: manuel.collado. od iguez@se gas.es
Lau aSánchez,Depa amen odeZoología,
Gené icayAn opologíaFísica,Facul adde
Ve e ina ia,Uni e sidadedeSan iagode
Compos ela,Lugo,Spain.
Email: lau aelena.sanche[email p o ec ed]
An ónBa ei o‐Iglesias,Depa men o 
Func ionalBiology,Facul yo Biology,
CIBUS,Uni e sidadedeSan iagode
Compos ela,15782San iagodeCompos ela,
Spain.
Email: an on.ba ei [email protected]
Funding in o ma ion
Fundinga  helabo a o yo M.C.is
p o idedby heMinis e iodeCiencia,
Inno aciónyUni e sidades,Fondos
Eu opeosdeDesa olloRegional(FEDER)
(RTI2018‐095818‐B‐100).Wo kin he
labo a o yo A.B.‐I.was undedbyg an s
om heXun adeGalicia(2016‐PG008)
and hec owd undingpla o mP ecipi a
(FECYT;2017‐CP081).Thelabo a o yo L.S.
issuppo edby heRegionalGo e nmen 
Xun adeGalicia(ED431C2018/28).
Abs ac
Cellula senescence is a s ess esponse ha limi s he p oli e a ion o damaged cells
by es ablishing a pe manen cell cycle a es . Di e en s imuli can igge senescence
bu excessi e p oduc ion o impai ed clea ance o hese cells can lead o hei accu‐
mula ion du ing aging wi h dele e ious e ec s. Despi e his po en ial nega i e side o
cellsenescence,i sphysiological oleasap o‐ egene a i eandmo phogene ic o ce
has eme ged ecen ly a e he iden i ica ion o p og ammed cell senescence du ing
emb yogenesisanddu ingwoundhealingandlimb egene a ion.He e,weexplo ed
heconse a iono  issueinju y‐inducedsenescenceinamodelo complex egen‐
e a ion, hezeb a ish.Finampu a ioninadul  ishled o heappea anceo senescen 
cellsa  hesi eo damage,and hei  emo alimpai ed issue egene a ion.Despi e
manyconcep ualsimila i ies, his issue epai  esponseisdi e en  omde elop‐
men al senescence. Ou esul s lend suppo o he no ion ha cell senescence is a
posi i e esponse p omo ing issue epai and homeos asis.
KEYWORDS
cellula senescence, egene a ion, issueinju y,zeb a ish
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1 | INTRODUCTION, RESULTS,
DISCUSSION
Cellula senescence is a e minal cell esponse consis ing on he imple‐
men a iono ape manen cellcyclea es and heacquisi iono ase‐
c e o ypheno ypewi hcell‐ o‐cellcommunica ionp ope ies(Collado,
Blasco,&Se ano,2007;Muñoz‐Espín&Se ano,2014).Exhaus ion
o  hep oli e a i ecapaci yo  hecellleads osenescence,and he
accumula ion o hese damaged cells in issues om old indi iduals is
conside edakeyelemen in hep ocesso aging( anDeu sen,2014).
Despi e hisde imen ale ec , hesenescence esponsehasabene‐
icial side p o ec ing damaged cells om p oli e a ing. This is consid‐
e ed hebasiso i s umo ‐supp essi e unc ion(Colladoe al.,2007;
Collado&Se ano,2010).The ecen iden i ica iono de elopmen‐
ally p og ammed cell senescence du ing emb yogenesis expanded
ou  iewo  heposi i eac i i ieso  his esponse(Muñoz‐Espíne al.,
2013;S o e e al.,2013).Senescencedu ingde elopmen p omo es
cell u no e , issue emodeling,and,pa adoxically,g ow h.Asimila 
posi i ep o‐mo phogene icac i i y o cellsenescencehasbeensug‐
ges ed oope a edu ingskinwoundhealinginmice(Dema iae al.,
2014)anddu inglimb egene a ioninsalamande s(Yun,Da aapil,&
B ockes,2015).Senescen cellsseem oappea a woundsi esa e 
inju y ohelpp omo eop imalwoundhealing(Yun,2018).
He e,wedecided oe alua e hesenescence esponsein he
con ex o issue inju y using an animal model o complex issue e‐
gene a ion, hezeb a ish.Tos udysenescencea e  issuedamage,
weampu a ed hepec o al ino adul  ish(a ound1yea old)a ap‐
p oxima ely 50% o i s leng h and ollowed egene a ion wi h ime
(Figu e1a).Wes ained ins o senescence‐associa edbe a‐galac‐
osidase(SAbe aGal), hemos widelyusedma ke o senescence
FIGURE 1 Pec o al inampu a ion
induces ea u es o cell senescence.
(a)Schema ic ep esen a iono  he in
ampu a ion sys em used h oughou
hes udy.(b)Rep esen a i e
pho omic og aphs o ins s ained o
SAbe aGalo phospho‐his one3(P‐H3,
igh panel)a e ampu a ions(NA:
nonampu a ed;8,16,and30dpa:days
pos ampu a ion).Co‐s ainingo P‐H3
wasdonea 8dpa.A owheadshows
heampu a ionplane.(c)Schema ic
ep esen a ion showing he di e en
ypes o samples used in he s udy
(NA:nonampu a ed;A:ampu a ed;
DIS:dis ala ea;PROX:p oximal).(d)
SAbe aGalac i i ymeasu edusing
Galac onsubs a ea e 8,16,and
30dayspos ampu a ion(dpa)( om5–10
animalspe condi ion).(e)Exp ession
le elsbyQPCRo cdkn1a(le panel)and
cdkn2ab( igh panel)genes ela i e o he
housekeeping gene ps11a e 8,16,and
30dayspos ampu a ion(dpa).Resul s
a e p esen ed as mean ± SD ***p<.001,
**p<.01,*p<.05,n.s.nonsigni ican
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DA SILVA‐ÁLVAREZ E AL.
(Dim i e  al., 1995),a e  8,16,o  30days pos ampu a ion (dpa),
a ime poin in which ins we e comple ely egene a ed. Con ol
s ainings we e pe o med on he con ala e al unampu a ed in o
immedia ely a e ampu a ion o disca d a i ac s de i ed om un‐
speci ics ainingo damaged issue.Finsa 8dpashowedin ense
blues ainingcompa edwi hligh bluea 16dpaandcomple elyab‐
sen s aininga 30dpa(Figu e1b).Immunohis ochemicalco‐s aining
wi hphospho‐his one3(P‐H3),ama ke o p oli e a ion,a 8dpa
con i med ha  heSAbe aGal‐posi i ecellswe eno p oli e a ing
(Figu e 1b).To u he  con i m hese esul s,we used an al e na‐
i esenescencede ec ionme hodmo eamenable o quan i ica‐
ion, u ilizing Galac on, a chemiluminescen  subs a e (Bassaneze,
Miyakawa,&K iege ,2008).Wecollec edampu a edandnonam‐
pu a ed ins a di e en imes du ing egene a ion and spli he
ampu a ed insin op oximal(close  o hebody)anddis al( he e‐
gene a eda ea)pa s(Figu e1c).Again,weobse ed ha 8dpawas
he imepoin  ha p oducedas onge SAbe aGal eac ionand his
ac i i ywas es ic ed o hedis alpa o  he in, hea eawhe e
egene a ion akesplace(Figu e1d).Incon as , hep oximala ea
o  he8dpa inand hedis alo p oximala easo 16and30dpa ins
we emos lynega i e(Figu e1d).
Wealsoex ac edRNA omampu a eddis alandp oximal ins
andunampu a ed ins, ocheck o  heexp essiono somegenes
ha ha e been linked o he induc ion o senescence in di e en
species (Collado & Se ano, 2006; He nandez‐Segu a, Nehme,
&Dema ia,2018)andinzeb a ish(Donninie al.,2010;Xiae al.,
2014).Simila  oou  esul swi h heSAbe aGalde ec ion, hedis al
pa o 8dpa insshowedhighe exp essionle elso cdkn1a and cd-
kn2ab han he p oximal pa o ampu a ed ins o he unampu a ed
con ala e al in (Figu e 1e). The exp ession o  hese senescence
ma ke s e u ned ono malle elsa e 16and30dpa,inlinewi h
ou obse a ionsusingSAbe aGal.
Insumma y, hese esul ssuppo  heno iono a ansien in‐
duc ion o cell senescence du ing in egene a ion as judged by in‐
c easedSAbe aGalac i i yandup egula iono  heexp essiono 
key senescence genes such as cdkn1a and cdkn2ab.Asimila  an‐
sien induc ion o senescence has been p e iously epo ed du ing
zeb a ishhea inju yand egene a ion(Bedna eke al.,2015).
FIGURE 2 Remo al o senescen cells
impai s in egene a ion.(a)Schema ic
ep esen a ion o he expe imen al
s a egy ollowed o analyze he e ec o
emo ing senescen cells om ampu a ed
insa e incuba ionwi hABT‐263 o 
48o 72h ,o  ea edwi h ehicle
(VEH).(b)SAbe aGalac i i ymeasu ed
usingGalac onsubs a ea 8days
pos ampu a ion and a e ea men wi h
ABT‐263 o 48o 72h ,o wi h ehicle
(VEH)( om5–10animalspe condi ion).
(c)Exp essionle elsbyQPCRo cdkn1a
(le panel)andcdkn2ab( igh panel)genes
ela i e o he housekeeping gene ps11 a
8dpaanda e  ea men wi hABT‐263
o 48o 72h ,o wi h ehicle(VEH).
(d)Leng ho  egene a e(%) eachedby
ampu a ed insa 8dayspos ampu a ion
anda e  ea men wi hABT‐263
ela i e o un ea ed ampu a ed ins ( i e
animalspe g oup).(e)Rep esen a i e
pho omic og aphs o la al ins s ained o
SAbe aGalo p21,24h a e ampu a ion
andcon ol in(CTRL).Scaleba s:
SAbe aGAL:200µm;p21:75µm.Resul s
a e p esen ed as mean ± SD ***p<.001,
**p<.01,*p<.05,n.s.nonsigni ican
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T igge ing senescence a e issue inju y could ha e posi i e o
nega i e e ec s on he egene a i e capaci y o he damaged is‐
sue,due oi spo en ialp o‐ egene a i eandan i‐p oli e a i eac‐
i i ies, espec i ely(He&Sha pless,2017).Todi ec lyassess he
oleo senescenceinduc iondu ing inampu a ion,wedecided o
induce he emo al o hese senescen cells om ampu a ed ins.
Fo  his,we ea ed ish o 48o 72h wi hABT‐263(Na i oclax),a
senoly iccompound ha byinhibi ing heBcl‐2an iapop o ic am‐
ily o p o eins igge s speci ically he dea h o he senescen cells
(Change al.,2016).Wede e mined heac i i yo  heSAbe aGal
enzyme in ex ac s om unampu a ed ins as con ol and om he
p oximal and dis al egions o ampu a ed ins ha we e p e iously
ea edwi hABT‐263 o 48o 72h o  ha we eincuba edwi h
ehicleasanega i econ ol(Figu e2a).ABT‐263 ea men caused
a educ ioninSAbe aGals ainingandaconcomi an induc iono 
apop osisin he egene a inga ea,asde e minedbyTUNELs aining
(Figu eS1A–C).Wequan i iedSAbe aGalac i i ya 8dpa, heday
a whichwehadobse ed hepeako senescenceinduc ion.We
con i med heinduc iono SAbe aGalac i i yin he ehicle‐ ea ed
ish and obse ed ha he ac i i y p esen in he ex ac s om he
egene a ing(dis al) egionwasblun edby heABT‐263 ea men 
(Figu e2b).Fu he mo e,mRNAexp essionanalysiso cdkn1a and
cdkn2aba e ABT‐263 ea men alsocon i med hed as ic educ‐
ion in he le els o hese senescence ma ke s a he egene a ing
a eaa e 48and72h o incuba ion(Figu e2c).
These esul s clea ly show ha i is possible o emo e senes‐
cen cells om he egene a ing a ea o inju ed ins by ea ing ish
wi h hesenoly iccompoundABT‐263,sowewonde edwha was
hee ec on egene a ion.Fo  his,wede e mined he egene a‐
i ecapaci ybymeasu ing heleng ho  egene a ea 8dpain ish
ea edwi hABT‐263 o 48o 72h o  ehicle.Thisanalysis e‐
ealed ha  he emo alo senescen cells byABT‐263 ea men 
clea ly impai ed egene a ion,wi hampu a ed ins in ish ea ed
wi h ABT‐263 showing a clea  educ ion in he leng h o  egen‐
e a e compa ed wi h he one eached in ehicle‐ ea ed animals
(73.67%±14.92%and62.57%±12.87%a e 48o 72h , espec‐
i ely)(Figu eS1DandFigu e2d).Apop osishasbeenshown obe
ac ucialp ocessdu ing in egene a ioninzeb a ish(V iz,Rei e ,&
Gallio ,2014).SinceABT‐263inhibi sp o einso  heBcl‐2 amilyand
hiscouldin e e ewi h hep o‐ egene a i eapop osis esponse,
wedecided ouseanal e na i esenoly ic ea men ,que ce in(Zhu
e al.,2015).T ea men wi hque ce inled oasimila  educ iono 
SAbe aGals ainingandanimpai ed egene a ion(Figu eS1E–G).
The ecen disco e y o cell senescence du ing emb yo de el‐
opmen as pa o a de elopmen al p og am poin s o a ole o se‐
nescence as a mo phogene ic and p oli e a i e o ce (Yun, 2018).
Senescenceinduc iondu ingadul  issueinju ycouldha e esul ed
om hee olu iona yco‐op iono  hisde elopmen alp og am e‐
ained du ing adul hood. To u he cla i y he occu ence o senes‐
cence du ing de elopmen  and issue inju y, we es ed senescence
induc ion in 3 dp ish la ae a e a comple e spinal co d ansec ion
a he le el o he anal po e which also damaged he su ounding body
wall(musclesandskin).A 2dayspos lesion(5dp animals),a e y
s ongSAbe aGals ainingappea edin heskinandbody‐wallmuscles
only a he inju y si e in lesioned animals and no in con ol unlesioned
animals,o inpo ionso  he unkaway om heinju ysi einle‐
sionedanimals(Figu eS2H).Thus, issueinju y‐inducedsenescence
isno anexclusi ep ope yo  inampu a ion,sinceadi e en kind
o auma ic inju y induces also cellula senescence in he skin and
muscles o he unk in zeb a ish.
In e es ingly,andincon as  olimbsinmice(Muñoz‐Espíne al.,
2013;S o e e al.,2013), insa enega i e o senescencema ke s
du ingzeb a ishde elopmen (Villia de al.,2017).Howe e ,am‐
pu a ion o he caudal in o 2 dp la ae p oduced a clea ly posi i e
eac ion o SAbe aGalac i i yandp21exp ession( hep oduc o 
cdkn1agene)(Figu e2e,andFigu eS1I).These esul ssugges  ha 
de elopmen al senescence and issue egene a i e cell senescence
a e di e en cell esponses igge ed by di e en s imuli ha migh
sha e some ea u es such as hei posi i e ole p omo ing issue e‐
modelingandg ow h.Howe e ,ou da adono allowus odis in‐
guish be ween a ole in wound healing o du ing egene a ion.
Insumma y,ou  esul slendsuppo  o heno ion ha  issue
inju y‐inducedsenescenceisaposi i e esponse ha p omo es e‐
gene a ion no only du ing mouse skin wound healing o salamande
limbampu a ion,bu alsoinzeb a ish,awidelyusedanimalmodelo 
complex egene a ion.
ACKNOWLEDGMENTS
WeacknowledgeMa íaO e o o expe  echnicalassis ancewi h
his ologicalanalysis.ABT‐263wasagene ousgi  omAbb ie.M.C.
isa“MiguelSe e II”in es iga o (CPII16/00015).
CONFLICT OF INTEREST
Au ho sdecla enocon lic o in e es .
AUTHOR CONTRIBUTIONS
S.DS.‐A.pe o med andin e p e edmos  o  he expe imen sand
helpedw i ing hemanusc ip .J.G.‐V.,D.S.‐C.andA.Q.helpedwi h
expe imen s.A.B.‐I.,L.S.andM.C.designed heexpe imen s,in e ‐
p e ed he esul s and w o e he manusc ip .
ORCID
Manuel Collado h ps://o cid.o g/0000‐0002‐0330‐0880
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SUPPORTING INFORMATION
Addi ional suppo ing in o ma ion may be ound online in he
Suppo ingIn o ma ionsec iona  heendo  hea icle.
How o ci e his a icle:DaSil a‐Ál a ezS,Gue a‐Va elaJ,
Sob ido‐CameánD,e al.Cellsenescencecon ibu es o
issue egene a ion in zeb a ish. Aging Cell. 2020;19:e13052.
h ps ://doi.o g/10.1111/acel.13052