Towards
deciphering
variations
of
heart
regeneration
in
fish
Anna
Jazwinska
and
Simon
Blanchoud
Amongadultvertebrates,thezebrafishpresentstherather
exceptionalcapacitytoefficientlyregenerateitsheartafter
injury.Thisbonyfishhasthusbecomealeadinggeneticmodel
organismtoelucidatethenaturalmechanismsofsuccessful
cardiacrestoration.Givenitspotentialbiomedicalsignificance,
parallelanalysesbetweenzebrafishandmammalsareaiming
attheidentificationofthepermissiveandrestrictivefactors
modulatingtheunderlyingcardiomyocyteproliferation.The
recentdiscoverythatsomeotherbonyfishspecieshavea
lowerregenerativecompetencethanzebrafishopensnew
opportunitiesforcomparativestudieswithinaframeworkof
similaranimalphysiologyandorganstructure.Here,wereview
recentlyidentifiedmodulatorsofcardiomyocyteproliferationin
zebrafishandhighlighttheresultsobtainedbythiscomparative
approach. Address
DepartmentofBiology,UniversityofFribourg,CheminduMuse´e10,
1700Fribourg,Switzerland
Correspondingauthor:Jazwinska,Anna(anna.jazwinska@unifr.ch)
CurrentOpinioninPhysiology2020,14:21–26
ThisreviewcomesfromathemedissueonRegeneration
EditedbyCatherinaGBecker,ThomasBeckerandJosephCWu
ForacompleteoverviewseetheIssueandtheEditorial
Availableonline27thNovember2019
https://doi.org/10.1016/j.cophys.2019.11.007
2468-8673/ã2019TheAuthors.PublishedbyElsevierLtd.Thisisan
openaccessarticleundertheCCBYlicense(http://creativecommons.
org/licenses/by/4.0/).
Introduction
Theheartisoneofthemostimportantvertebrateorgans duetoitsvitalblood-pumpingfunction.Consequently,a prompt and efficient mechanism to heal heart injuries would be particularly beneficial. A restoration of the myocardium to a pre-injury state obviously represents theoptimalstrategy.Yet,cardiacregenerationisabsentin adult mammals and has only been observed in a few anamnioticvertebrates,suchaszebrafishandaxolotls[1]. As the heart lacks competent cardiac stem cells, the regenerativemechanismsolelyreliesontheproliferative capacity of pre-existing cardiomyocytes (CMs) [2–5]. Understanding how the cellular plasticity of CMs is modulated is thus of major scientific and therapeutic relevance.
In non-regenerative hearts, such as in adult mammals, damageleadstoscarring,whichcausesvaryingdegreesof
cardiac dysfunctions including heart failure [6]. This imperfectrepairseemstobeaconsequenceofthe inabil-ityofmaturemammalianCMstoefficientlymultiplyfor restoringthemissingtissue[4].Indeed,mammalianCMs substantiallydiminishtheiraccesstothecellcycleafter theneonatalstage[7].Nevertheless,theinherentrenewal of some mature CMs can be experimentally enhanced by hypoxic conditions, pharmacological treatment, and geneticmodificationsofmolecularpathways[8–10].Yet, itisstilldebatedwhethermammalianCMscouldreacha proliferative statesufficientforregeneration.
Bycontrast,thezebrafishcannaturallyregenerateitsheart afterdifferenttypesofinjuries,andrecoverthe functional-ity of thisorgan, as recentlyreviewedin[1,11–14].For example, cryoinjured hearts regenerate most of their damagedtissuewithin30–60days[15],andtheircomplete restorationmayrequire130–180days[16,17].Thisprocess is sustained by CMsthat are stimulatedupon injury to revert to a less differentiated state, whichis thought to facilitate cell proliferation and morphogenesis [18–21]. Myocardialregenerationisaccompaniedbytheactivation ofothertissuetypesoftheheart,suchastheendocardium, epicardium,bloodandlymphaticvasculature,nervesand immune system [22–30].Thus, theintrinsic features of CMsandextrinsicsignalsfromothertissuescontributeto therestorativeoutcome.Consequently,identifying, char-acterizingandcontrollingsomeofthesefactorsconstitute majorscientificinterest.
Cellular
complexity
and
polyploidy
of
cardiomyocytes
as
obstacles
for
proliferation
Increased structuraland physiologicalcomplexityofthe hearthasbeenproposedtobeoneofthelimitingfactors forregenerationinmammals[1,13].Becausethe metab-olism of endothermic organisms requires more energy, mammalshaveacquiredamoreperformantheartthrough enlargement and specialization of their CMs. Although biggerCMscanbebetteratgeneratingcontractileforces, their structuralcomplexity imposes more challengeson celldivisionand plasticity[31].Moreover, the mamma-lian cardiac hypertrophy is typically associated with a polyploidization event,meaningthatthesetof chromo-somes is multiplied without a subsequent cell division [32]. This polyploidization coincides with the loss of proliferative capacity of the mammalian myocardium aroundthetimeofbirth,suggestingacorrelationbetween bothchanges[33].The lossoftheproliferativecapacity canthusbeconsidered,atleastto acertain extent,as a trade-offforfosteringthecontractiletissuewith special-izedandpolyploidCMs[1].
Tworecentstudiestestedthishypothesisinthezebrafish heart, which nearly entirely comprises diploid CMs [34,35].First,Gonzalez-Rosaetal.investigatedif experi-mentally inducedpolyploidy issufficient to affectheart regeneration in the zebrafish [35]. They established a transgenic approach to inhibit CM division during ontogenic growth by the transient overexpression of a dominant-negative form of Ect2 (dnEct2), a Rho GEF proteinrequiredforcytokineticringassembly.Thismodel yieldedmosaiczebrafishheartswithdifferentproportions of polyploid CMs, which were lineage-tracedthrough a Cre-loxbasedsystem.Followingcardiacinjury,polyploid CMs contributed to the regenerated tissue much less efficientlythandiploidCMs.Moreover,heartswithahigh percentage of polyploid myocardium (>50 %) failed to regenerate. Thus, polyploidization interfered with the robustproliferativecapacityofthezebrafishheart. Another recentstudy has reached similar conclusions by inducingpolyploidCMsinzebrafishthroughadministration of thyroid hormone [34]. This chemical treatment increasesthefrequencyofbinucleatedCMsbyfivefoldin the zebrafish heart. After injury, these hearts displayed reducedCMproliferationandblockedregeneration.Thus, polyploid zebrafish CMs tend to lose their proliferative efficiency,similarlytotheirmammaliancounterparts[36]. Interestingly, a possible link between altered thyroid hormone availabilityand the loss of cardiac regenerative capacityhasrecentlybeendescribedinfrogs(Xenopuslaevis) [37].Theunderlyingcausesofregenerativeimpairmentdue topolyploidyandthyroidhormoneremaintobeelucidated. Inaddition,researchonzebrafishhas identifiedanumberof signalling pathways, DNA-binding proteins, epigenetic factors, microRNAs and extracellular matrix proteins required for heart regeneration, as comprehensively reviewedinRef.[11].Theinterruptionofthese endoge-nousmolecularfactorstypicallyimpairsCMproliferation and preventsregeneration.However, identifying exoge-nousstimulators ofCMproliferation providesa comple-mentaryapproachtodissectthemechanismsunderlying heartregeneration.
Boosting
cardiomyocyte
proliferation
by
vitamin
D
and
preconditioning
in
zebrafish
Although zebrafishperfectlyregenerate theirheartafter injury, two recent studies have succeeded in further improving this dramatic process by two different approaches,bothresultinginanincreasedCMproliferative activity.Inthefirststudy,Hanetal.demonstratedthe pro-mitotic role of the steroid pro-hormone Vitamin D by administrationofanexogenousanalogue,called alfacalci-dol [38]. This effect was blunted by the inhibition of ErbB2signalling,areceptorofNeuregulin1[39], indicat-ing that Vitamin D partially acts through this cascade. Moreover, blockade of the Vitamin D receptor (VDR) impairs the regenerative process. During ontogenesis,
genetically induced activation of VDR signalling in the heartleadstocardiomegaly,aphenotypecharacterizedby anenlargedandthickenedmyocardialwall.Theseresults highlighttheimportanceoftheendocrinesystemduring cardiac regeneration [3,40,41]. In humans, Vitamin D signallinghasbeenreportedtoprotectischemic myocar-diumthroughanti-inflammatoryandanti-apoptotic mech-anisms [42]. Vitamin D could, thus, have a conserved beneficialpro-regenerativefunctioninvertebrates. In the second study, our laboratory hasshown thatthe CilliaryNeurotrophicFactor(CNTF)cytokineisa stimu-latingfactorinthecontextofcardiacpreconditioningand regeneration in zebrafish [43]. Preconditioning is a ‘resilience’ mechanism that is triggered by exposure to lowdosesofaharmfulstimulusinordertoenabletissuesto better withstand thedeleterious effects of more severe subsequentinjuries[44].Weinducecardiac precondition-inginadultzebrafishbyperformingthoracotomyafewdays beforeventricularinjury[45].Thisprocedureincreasescell survival and CM proliferation during the first week of regeneration through upregulation of epicardial factors, suchasCNTF[46,47].Remarkably,asingleinjectionof CNTFintothepericardialcavityissufficienttotriggerCM proliferationintheintactheart[43].Mutationofthecntf genesuppressesthepreconditioningeffectsafter thoracot-omy.Intheregeneratingzebrafishheart,deliveryofCNTF before ventricular cryoinjury improves the initiation of regenerationvia reducedcellapoptosisandboostedCM proliferation.ThedownstreamtargetsofCNTFinclude JAK/STAT3signalling,astheinhibitionofthispathwayis sufficienttosuppresstheeffectsofthecytokine. Interest-ingly,overexpressionofadominantnegativeSTAT3has beenshowntorestrictCMproliferationduring regenera-tion, but notduring normalgrowthin zebrafish [48].In mammals,exogenousadministrationoftheCNTFprotein isknowntoexertprotectiveeffectsforneuraltissuesandto promotemyoblastproliferation[49].Themechanismsof CNTF-basedpreconditioningarethuspotentially evolu-tionarilyconserved.
Taken together, these recent studies suggest the exis-tenceofphysiologicalandparacrinemechanismsthatcan boost the proliferative programs in the zebrafish heart. Theidentificationofadditionalpositivemodulatorsanda deepercomprehensionofthecardioprotectivemachinery willprovideimportantlinesofresearchwiththeultimate goalofmimickingsuchprocessesinmammals.
Insights
from
comparative
studies
of
heart
regeneration
in
different
fish
species
CMproliferationisthekeyprocessforheartrestoration. In order to understand the molecular causes regulating CMproliferation,a promisingapproach isto determine the similarities and differences between the injured hearts of regenerative and non-regenerative organisms. Anexampleofsuchcomparisonsistherecentcreationofa
common platform for transcriptomicdatabases to facili-tate cross-experiment analyses [50]. This interspecies approach is elegantly represented by a study in which zebrafishregeneration-specificenhancersareactivatedin the post-injury tissues of neonatal mice, suggesting a sharedpotential[51].However,theimportanttaxonomic distance betweenzebrafish andmammalsmight leadto organismalandgenomicdifferencesthathinderthe iden-tificationof factorsspecificallylinkedtoregeneration. Anumberoffishspecieshavebeenshown toefficiently restoreavarietyoforgansinadditiontotheirheart[52]. Interestingly, while regenerative capacities seem to be highly conserved for some bodyparts (e.g. fins), others vary between species (e.g. heart, Figure 1). Therefore, bony fishes provide a morphologically coherent and genetically focusedcontextforinterspeciesresearch. One of the first reported interspecies analysis on heart regenerationwasperformedbetweenzebrafishandmedaka (Oryziaslatipes)[53],twospeciesthatseparatedduringthe earlyteleostradiationapproximatively250millionyearsago [54](Figure1).After cardiacinjuries,medakareactwithhigh
mortality, excessive fibrosis and health impairments [53,55].Inadditiontothesephenotypes,lowCM prolifer-ationandalackofrevascularizationareobserved,indicating anabsenceofheartregeneration.Interestingly,the regener-ativefailurewasalsoassociatedwithdelayedmacrophage recruitment, along with suppressed neutrophil clearance. Usinginterspeciestranscriptomicanalyses,Laiand collea-gues identified a reduction in the immune response comparedtozebrafish[55].Theauthorsthenconfirmed the significance of this difference by improving cardiac regeneration in medaka through polyIC injections. This treatment,whichstimulatestheToll-likereceptorsignaling, results in enhanced CM proliferation, neovascularization andscarresolution.Thesefindingsnotonlysuggestacrucial rolefortheimmunesysteminpro-regenerativeprograms, buttheyalsodemonstratethevalueofinterspeciesanalysis toidentifymodulatorsofregeneration.
Asecond andparticularlyinterestingstudyhasrecently been elaborated using intraspecies comparisons of the Mexican cavefish (Astyanax mexicanus) [56]. This species, which had a common ancestor with zebrafish approximately180millionyearsago(Figure1),includes
Figure1 Cladistia Teleostei Clupeocephala Euteleostei Ovalentaria Actinopterygii Otophysa Osteoglossomorpha Protacanthopterygii 400 300 200 100 0 Mya Polypteriformes Osteoglossiformes
Cypriniformes (e.g. zebrafish) Characiformes (e.g. Mexican cavefish) Gymnotiformes
Siluriformes Salmoniformes Cichliformes
Cyprinodontiformes (e.g. platy) Beloniformes (e.g. medaka) Blenniformes
P. senegalus, P. ornatipinnis P. buchholzi
D. rerio, D. aequipinnatus, C. carpio, C. auratus A. mexicanus
A. leptorhynchus, E. virescens, S. macrurus K. bicirrhis
O. mykiss, S. salar O. mossambicus, O. niloticus X. maculatus, G. affinis, M. loati O. latipes
S. pavo
Current Opinion in Physiology
Phylogenyofselectedordersofbonyfishesandtheirreportedregenerativecapacities.AportionofthephylogenetictreeofActinopterygii(ray-finned
fishes)isdepictedandoverlaidwithrelevanttaxonomicgroupsandthecorrespondingevolutionarytimeexpressedinmillionyearsago(Mya).Orders,
whichwereselectedashavingatleastonespecieswithareportedregenerativecapacity,aredisplayedontherightsiteofthefigure.Thefirstspecies
listedineachorderwasusedtocreatetheschematicdrawingoffish.Foreachorder,colour-codedboxesindicatethereportedregenerative
capacitiesforthefin,thenervoussystemandtheheart.Colour-codeisgreenforefficientregeneration,yellowforsuspectedregeneration,redfor
shownabsenceofregenerationandgreyforabsenceofpublisheddata.PhylogenyisbasedonRef.[54],regenerativecapacitiesonRefs.
twodistinctmorphotypes.Inadditiontothetypicalriver A.mexicanus,asubpopulationhasevolvedtoinhabitcave ponds where they got trapped following transient floodingsbetween1and3millionyearsago[57].These fish have adapted theirbehavior, metabolism and mor-phologytodarkenvironments.Surprisingly,thecavefish havenotonlylost theireyesandskin pigmentationbut alsotheirabilitytoundergoheartregeneration[56].By comparing non-regenerative cave population with the regenerative river population using quantitative trait locus analysis, the authors have identified three loci putativelylinkedwithcardiachealing.Oneofthesegenes islrrc10, aleucine-richrepeatprotein. However,further analysesareneededtodeterminethemechanisticcauses of the diminished cardiac regeneration. The Mexican cavefish represents a very promising model to study thefast evolutionaryloss of heart regenerationcapacity andthusaplatformtoidentifycentralmodulatorsofthis process.
Genetic changes associated with adaptation to life in darknesscouldpossiblybelinkedtothelossofsystemic factors required for stimulation of CM proliferation. In particular,itwouldbeinterestingtoinvestigatewhether cavefishdisplayaninsufficiencyinVitaminD,assuggested by the aforementioned work in zebrafish [38].Indeed, sunlightexposureisprobablyrequiredforthesynthesisof thishormoneinfish,asrainbowtroutrearedinthedarkfor twoyearsdevelopadeficiencyinVitaminD,whichcanbe rescued by exposure to artificial light [58]. Thus, the Mexicancavefishmighthaveevolvedmetabolicadaptations thatarenotcompatiblewith thiscardiacpro-regenerative pathway.Itwouldbeinterestingtotestwhetherexogenous administrationofVitaminDwouldrestoreheart regenera-tionincavefish,andifconstantdarknesspreventscardiac restorationin zebrafish. More generally,it willbe highly relevantfor myocardialresearchtoassessandunderstandthe evolution and modulation of the regenerative capacity amongfishes(Figure1).
Currently, heart regeneration has been assessed in a limitednumberoffishspecies.Inthiscontext,itis impor-tanttonotethatbecausenegativeresultsarenotablymore difficulttopublish,otherspeciesoffishmighthavebeen sampledbuttheirabsenceofregenerationneverreported. Cypriniformes is the most assessed phylogenetic order with two additional fish species shown to regenerate theirheartsafter cauteryinjury, namelythegiantdanio (Devarioaequipinnatus)andthegoldfish(Carassiusauratus) [59,60].TogetherwiththedatafromtheCharaciformes A.mexicanus,theseresultscouldsuggestthatheart regen-erationisconservedinOtophysafishes(Figure1).More distantly, CM proliferation has been detected in the SalmoniformesSalmosalarandPolypteriformesPolypterus senegalus,butassessingtheefficiencyoftheregenerative processas a wholewill requirefurtheranalysisin these species[61,62].
Conversely,it is notyet known if theabsenceof heart regeneration observed in medaka is conserved beyond theBeloniformesorder.Toinvestigatethisquestion,our laboratory is currently studying heart regeneration in a species of the related Cyprinidontiformes platyfish (Xiphophorusmaculatus)(Figure1).Togetherwithstudies in more distant orders, such as Cichliformes or Blenni-formes,ourresultscouldhelpdeterminewhetheralackof heartregenerationiscommontoOvalentariafishes.The examination of representative species of additional phylogeneticgroupswillilluminatenewfactors modulat-ingheartregeneration.
Conclusions
UnderstandingthemolecularmechanismsunderlyingCM proliferationinvertebratesisofmajorscientificand thera-peutic interest. Zebrafish is the leading genetic model organisminthisfield,andthestudyofitsdramatic regenera-tivecapacitieshasbroughtnumerousinsightsinto myocar-dialresearch.Toidentifyconservedmodulatorsofcardiac regeneration, zebrafish data are typically compared with those of non-regenerative species, and of mammals in particular. However, the distant phylogenetic separation betweenthesetwotaxaislinkedwithmajorphysiological andanatomical differences potentially unrelated to heart regeneration.Inthiscontext,comparisonsbetweenclosely relatedspecieswithvaryingdegreesofregenerativecapacity areofparticularinterest.Recentstudieshavedemonstrated that heart regeneration is variable between fishes from differenttaxonomic families, as well as between distinct morphotypes.Theresultingcomparativeinterspeciesand intraspeciesanalysessuggestthatthecardiacrestorationis alsoregulatedbycurrentlyundeterminedorganismalfactors [26]. Sampling of additional fish species will open new avenuestoapproachthistopicand,inthelongterm,might bringcluesfornovelmedicalstrategies.
Financial
support
This work was supported by the Novartis Foundation forMedical-Biological Research andtheSwissNational ScienceFoundation,grantnumbers:310030_179213and PZ00P3_17398.
Conflict
of
interest
statement
Nothingdeclared.
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