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Perspective

Prostaglandin E2

Making More of Your Marrow

Allegra M. Lord Trista E. North Leonard I. Zon*

Stem Cell Program and Hematology/Oncology; Children's Hospital and DanaFarber Cancer Institute; HHMI; Harvard Stem Cell Institute; Harvard Medical School; Boston, Massachusetts USA *Correspondence to: Leonard I. Zon; Stem Cell Program, Hematology/Oncology; HHMI; Children's Hospital; Karp Family Research Building, 7; 1 Blackfan Circle; Boston, Massachusetts 02115 USA; Tel.: 617.919.2069; Fax: 617.730.0222; Email: [email protected] Original manuscript submitted: 09/27/07 Manuscript accepted: 10/03/07 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/5129

AbsTrAcT

We have recently demonstrated through a chemical screen in the zebrafish embryo that prostaglandin E2 (PGE2) is an evolutionarily conserved regulator of hematopoietic stem cell (HSC) number. These results have further been confirmed by in vitro and in vivo studies in the murine model. Bioactive PGE2 derivatives have potential clinical application to accelerate recovery of the hematopoietic system following chemotherapy or irradiation. Ex vivo expansion of HSCs prior to stem cell transplantation may improve reconstitution of hematopoiesis and immune function. This article aims to summarize current knowledge of PGE2-mediated regulation of blood cell homeostasis as well as to discuss the proposed use of PGE2 to expand hematopoietic stem cells for transplantation in the clinical setting.

HEMATopoIEsIs

Vertebratehematopoiesisoccursintwoconsecutivewaves,termedprimitiveanddefini tive.1The primitive wave originates in the yolk sac in mammals and birds, and in the intermediatecellmass(ICM)inzebrafish,andgivesriseonlytocellsoftheerythroidand myeloidlineages.Thedefinitivewaveproduceshematopoieticstemcells(HSCs)capable of generating and repopulating the entire hematopoietic system. Definitive HSCs have threemaincharacteristics:(1)theymaintainhematopoietichomeostasisthroughoutthe lifetimeoftheorganism,(2)theyarecapableofrecapitulatingallhematopoieticlineages followinginjuryand(3)theycanreconstitutehematopoieticlineagesinclinicalorexperi mentalsettingswhentransplantedintoahostlackingHSCs.Invertebrateembryos,the first definitive HSCs arise primarily from the aortagonadmesenephros (AGM) region (Fig.1).Intheadult,HSCsarefoundinthebonemarrowinmammals,andthekidney marrowinthezebrafish.Despitedifferencesinphysiologicallocationofthehematopoietic niche,thegeneprogramsutilizedineachtissuearewellconservedacrossspecies. HSCsarevaluableintheclinicalsettingforthetreatmentofhematologicalmalignan cies,immunodeficienciesandbonemarrowfailure,butareararepopulationintheadult bonemarrow.MuchprogresshasbeenmaderecentlyinidentifyingandisolatingHSCs, thoughefficienttechniquestoexpandfunctionallycompetentHSCsarestilllacking.A more thorough understanding of the processes that regulate HSC homeostasis will aid therapeuticmanipulationsofthesecells,andmayalsoshedlightontheprocessofleuke mogenesis,whichsharesmanyofthegeneprogramsutilizedinHSCregulation.

KEy words hematopoiesis,hematopoieticstemcell,pros taglandinE2,zebrafish AcKNowLEdgEMENTs TheauthorsthankW.Goessling,R.White,T. V. Bowman, Y. Zhou, and P. Nathanson for theircriticalreadingofthismanuscript.

prosTAgLANdIN sIgNALINg

Eicosanoidsignaltransductionpathwaysarehighlyconservedacrossvertebratespecies. Theprostaglandins,asubsetoftheeicosanoidfamilyofsignalingmolecules,areinvolved inanumberofphysiologicalprocessesinmanytissues.2Thereareseveralprostaglandin isoformsinvertebrates;ofthese,prostaglandin(PG)E2isamongthebestcharacterized andwillbethefocusofthisarticle.Prostaglandinsaresynthesizedfromarachidonicacid (AA)firstbycyclooxygenase(Cox)1or2,whichconvertAAintoPGH2.Thisprecursor PG is further processed by isoformspecific cytosolic or microsomal prostaglandin synthases (c/mPGES) to become PGE2 or one of several other effector prostaglandins. TherolesofCox1andCox2inprostaglandinproductiondonotwhollyoverlap;Cox1 appearstoberesponsibleforthemajorityofconstitutivesignaling,whileCox2actsinan induciblefashion.IthasbeensuggestedthatCox1andcPGES,andCox2andmPGES, 3054 CellCycle 2007;Vol.6Issue24

PGE2inBloodDevelopmentandHomeostasis

Figure 1. Expression of the conserved HSC marker runx1 by in situ hybridization at 36 hours post fertilization in a zebrafish embryo.

respectively, work in cooperation.3,4 This model may oversimplify the role of the two prostaglandin synthases, as increasing evidence implies that the requirement of each enzyme for PG production is specifictobothcelltypeandfunction. PGE2signalsineitheranautocrineorparacrinemannerthrough fourspecificGproteincoupledEprostanoid(EP)receptors.Positive signaltransductionreceptorsincludeEP1,whichtriggersmobiliza tionofintracellularCa2+,andEP2andEP4,whichbothstimulate cyclic AMP (cAMP) production. EP3 acts as a negative effector to inhibit cAMP.There is evidence to indicate that EP2 and EP4 are affected differently by PGE2; EP4 quickly becomes desensitized to PGE2andcannotbinditsmetabolites,whileEP2displaysnosuch desensitization and is able to bind several PGE2 metabolites with varying affinities.5This would imply that PGE2 signaling is regu lateddistinctlyonthelevelsofCox,PGES,andEPreceptorsthough noconclusiveresultshaveyetbeenproducedtosupportthismodel.

prosTAgLANdINs IN VAscuLATurE

Prostaglandins are well known for their role in vascular homeo stasis.2 PGE2 and PGI2 signaling regulate a complex interplay of vasoconstriction and vasodilation. Proper functioning of the Cox pathway is also required for the closure of the ductus arteriosus duringdevelopment,asdemonstratedbytheCox1,Cox2double knockout (KO) mouse6 as well as by the effects of Cox inhibi tors in human neonates.7 While both Cox1 and Cox2 KO mice were developed to reveal the requirement of each cyclooxygenase, researchinthisareawasconfoundedbyinuterodevelopmentinthe murinemodel;bothmaternalandsiblingcontributionstothefetal KO mouse partially compensate for loss of Cox activity and allow progressionthroughembryogenesis. Thezebrafishhasbeenausefulmodelfordevelopmentalstudies, astheembryoscanbestudiedfromtheonecellstageonwardsand develop ex vivo. In the fish, as in human cell culture experiments, Cox1 signal is required for normal endothelial tube formation.8 Interestingly, Cox1 is necessary for the proper formation of the dorsalaorta,8whichisthesitefromwhichdefinitiveHSCsarisein the AGM. Cox2 signaling, as mediated by PGE2, is necessary for angiogenesisandhasbeenimplicatedinincreasedcellmotilityand invasivenessinvariouscancers.9

in mature erythrocytes, playing a role in cellular stress response by regulatingK+effluxandcellsize.10,11Inaddition,theCoxpathway affects the ability of hematopoietic progenitor cells to selfrenew and differentiate. Murine studies have shown lymphoid progenitor maturationtobedependentuponCoxsignaling,12,13whilearecent studyinthezebrafishhasshownthatPGE2isrequiredforthedevel opmentoflymphoidprogenitors.14Studiesinhumancelllineshave implicatedPGasaregulatorofmyeloidprogenitormaturation.15,16 Addition of PGE2 to longterm murine BM culture produces a significant increase in the number of granulocyte and macrophage progenitors,17addingtotheevidencethatPGE2canaffecthemato poiesisatleastatthelevelofhematopoieticprogenitorcells. Research onthe effects ofPGE2in hematopoiesisoverthepast 30yearshasproducedvarying,oftenconflicting,results.Earlystudies showedpromiseforprostaglandinsaspotentenhancersofhemato poieticprogenitoractivity.PGE2wasshowntostimulateprogenitor proliferation in vitro in cell culture and after transplantation in a CFUSassay.18Subsequentinvivoresultsdiffered,however;injured mice injected with PGE2 showed no significant improvement in marrowrecoveryversuscontrolanimals.19Notably,inthisstudythe drugwasadministeredthroughdirectintramuscularinjection.Given theshorthalflifeofPGE2invivo,itisprobablethatthedrugwas metabolized before significant effects on the hematopoietic system could have occurred. Later studies using intravenous injections metwithconsiderablymoresuccess.Althoughanumberofgroups reportedinhibitoryrolesforPGE2onprogenitorcelldifferentiation in culture, PGE2 was administered in these studies repeatedly and overlongtermexposures.20,21Itwaslaterfoundthatincubationof humanBMwithPGE2forshortperiodsoftimecouldactuallystim ulate proliferation and differentiation of progenitor cells.22,23 The timing and dose of PGE2 treatment is an important consideration whenevaluatingtheeffectsonthehematopoieticsystem.Differences in methodology may account for conflicting results found in the literature. ThedevelopmentoftheCox2KOmouseenabledfurtherstudies to clarify the role of the PG pathway in hematopoietic reconstitu tion.Lorenzetalfoundthatalthoughhomeostatichematopoiesisin Cox2deficient mice was normal, reconstitution of hematopoietic lineages was seriously impaired following injury.24 Additionally, the marrow of Cox2deficient mice exhibited impaired formation of boneresorbing osteoclasts in culture.25 Interestingly, osteoclasts have since been shown to be an important part of the HSC niche in vivo,26,27 which may be one means by which the PG pathway regulatesHSCs.

prosTAgLANdIN ANd Hscs

In our recently published work,28 we performed a chemical screen using zebrafish embryos to find small molecules that could modifyHSCnumberinvivo.Inourscreen,severalsmallmolecules affecting the prostaglandin pathway emerged, including prosta glandinE2,whichisthemaineffectorprostanoidinthezebrafish.29 Embryostreatedwithexogenous16,16dimethylPGE2(dmPGE2), a longacting derivative of PGE2, exhibited a marked increase in HSC number. To better understand the mechanisms by which prosTAgLANdINs IN bLood prostaglandins can affect HSCs, we examined other components Prostaglandin E2 has long been noted to have a role in regu ofthePGpathway.Knockdownofcox1,cox2,orPGE2synthase lating hematopoietic homeostasis. Prostaglandin signaling is active resulted in decreased numbers of HSCs, further implicating PGE2 www.landesbioscience.com CellCycle 3055

PGE2inBloodDevelopmentandHomeostasis

Figure 2. Schematic representation of the experimental design for limiting dilution competitive repopulation transplantations.

intheregulationofHSCdevelopment.Cox1washighlyexpressed inthevascularniche,8whilecox2appearedtobeexpressedinthe HSCs themselves. These results suggest a differential role for the two cyclooxygenases, in which cox1 promotes development of the hematopoieticniche/vascularmicroenvironmentwhilecox2directly affects the development or proliferation of the HSC. Knockdown of cox2 did not completely ablate HSC formation, suggesting thatothersignalingmoleculesaresufficientforthedevelopmentof HSCs.Onepossibilityisthatcox2controlsselfrenewalpathways. Lossofcox2couldthereforeresultinprematuredifferentiationand lossofHSCs.Ongoingstudiesinourlaboratoryareinvestigatingthe meansbywhichcyclooxygenasesignalingspecificallyregulatesHSC selfrenewal,differentiationandnicheinteractions. In the course of our study, we determined that PGE2 signals throughboththeEP2andtheEP4receptorstopromotetheforma tion of HSCs. Both of these receptors are present in the AGM as well as in the HSC itself. It will be important to further examine the roles of these two receptors. Given the evidence for dual roles forEP2andEP4,5itispossiblethatthetworeceptorsrespondwith distinctdifferencestoPGE2.Perhapsthesemoleculesacttofurther theproposedcox1/2duality,translatingPGE2intoanichespecific orHSCspecificsignalthroughthestimulationofdownstreameffec tors.Thespecificrolesandlocalizationofeachreceptorneedtobe examinedinfurtherdetail. ThetargetsofPGE2alsohaveyettobefullycharacterized.Our data show that classical HSC and endothelial markers (i.e., runx1, cmyb, fli, flk) are all upregulated in response to overactivation of the PG signaling pathway, but whether these are direct or indirect pathwaytargetshasyettobedetermined.Ithasbeendemonstrated thatVEGFandbFGFactivitiesaremediatedbyPGsignaling.30,31 Itwouldbeinterestingtoexaminethepotentialcooperationofthese moleculeswithPGE2intheformationoftheHSC.Abetterunder standingofthemechanismbywhichPGE2regulatesHSCswillgive insightintohowwemightmanipulatethispathwaytherapeutically incasesofdysregulatedPGsignaling. Toextendourobservationstothemammaliansystem,weexam ined the effects of dmPGE2 on murine embryonic stem (ES) cell differentiationandinmousebonemarrowinjurymodels.Addition ofdmPGE2toEScellsincultureresultedinsignificantincreasesin thenumbersofmultipotentdefinitivehematopoieticprogenitors.In thecourseofourEScellstudies,weconfirmedthatthedoseofPGE2 is important.When ES cells were grown in high concentrations of PGE2, the compound had an inhibitory effect on differentiation. Wehypothesizethatathighdosesoruponrepeatedexposure,PGE2 3056

`freezes' the stem cell in a pattern of selfrenewal at the expense of differentiation, resulting in decreased numbers of progenitor and differentiated colonies.This model is analogous to results by Reya et al, which show that high levels of Wnt signaling lead HSCs to preferentially selfrenew rather than differentiate.32 The variability inPGE2concentrationsandlengthofexposureusedinpriorstudies mayaccountforsomeoftheconflictingresultswithregardtoPGE2 effectonstemandprogenitorcells. To explore the effects of PG signaling in vivo, we treated mice challenged with 5fluorouracil (5FU) with either dmPGE2 or selective inhibitors of Cox1 or Cox2 and monitored the effects on hematopoietic recovery. Treatment with dmPGE2 significantly improved marrow recovery rates, while inhibition of either cyclo oxygenase decreased recovery. These results correlated well with those detailed previously using the Cox2 KO mouse. We next performedlimitingdilutioncompetitivetransplantationassayusing murine bone marrow cells treated ex vivo with dmPGE2 (Fig. 2), andfoundthatdmPGE2treatedcellshadasignificantcompetitive advantage and a higher percentage of engraftment than untreated cells.Thiseffectwasnotonlylongtermandmultilineage,butalso serially transplantable (North, Goessling, and Zon, unpublished data), indicating that PGE2 affects functional stem cells, and not onlyhematopoieticprogenitorcells.Inordertoexaminewhetherthe effectofPGE2onHSCsmightbetoimprovehomingofHSCsto thehematopoieticniche,weperformedcelltracingexperimentsusing purified,labeledmurineckit+/sca1+/lin(KSL)cellsinjectedinto recipientmice.ContributionoflabeledcellstotheBMat12hours posttransplantation was not significantly different from controls, implyingthatPGE2treatmentdoesnotaffectstemcellhoming.We hypothesizethatPGE2increasestheselfrenewalcapacityofHSCs, priming transplanted HSCs to go through an additional round of duplication when they reach the niche before differentiating into multipotentprogenitors.Ourresultsfurthershowthatexvivoexpo sureofstemandprogenitorcellstoPGE2isaneffectivemeansof obtainingsignificantinvivoalterationinnumberofengraftedHSCs aftertransplantation.

THErApEuTIc IMpLIcATIoNs of pg/Hsc INTErAcTIoN

Currently, patients requiring treatment with HSCs due to hereditarydiseaseortheeffectsofcancertherapiescanachievehema topoieticrepairbyHSCtransplantation,whichincludesperipheral blood stem cell transplantation (PBSCT), bone marrow transplant (BMT), and umbilical cord blood transplant (UCBT). UCBT is 2007;Vol.6Issue24

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PGE2inBloodDevelopmentandHomeostasis

typically offered to patients only in cases where BMT or PBSCT arenotpossibleduetolackofamatcheddonor.Humancordblood (hCB)cellscanbestoredindefinitelyincryopreservationbanksand are readily available for transplantation when needed, reducing the time patients have to wait for transplantation. UCBT is also more tolerantofHLAmismatchthanBMT,leadingtoreducedincidence of graftversushost disease as well as an expansion of the pool of potentialdonorsforanyonepatient.33,34Ifadonormatchisfound, BMTremainsthepreferredmethodoftreatment,primarilybecause thesupplyoftransplantablecellsisnotrestricted,guaranteeingsuffi cientnumbersofHSCs.ThenumberofHSCsandprogenitorcells perunitofcordbloodismuchlowerthaninthebonemarrow,but forpatientsforwhomBMT/PBSCTisnotpossibleUCBToffersa tenablealternative.Toaddresstheproblemoflowerprogenitorcell number, two hCB units are currently transplanted per recipient, whichappearstoenhancehematopoieticrepopulation.Significantly, recentdatasuggestthatthestemandprogenitorcellsfromonlyone oftheseunitsmayengraftinthelongterm.35TheunengraftedhCB unitisbelievedtoprovidesupportintheearlystagesofrecovery. BecausePGE2isalreadyusedinvariousclinicalsettings,itpres entsanattractivepotentialtherapyforhumanpatientswithdepleted HSCs.AsPGE2exposureprovidesstimulationforthereconstitution of hematopoietic lineages from transplanted HSCs, one possibility wouldbetousethiscompoundasameansofimprovingtheeffec tivenessofcordbloodtransplants.ExvivotreatmentofhCBswith dmPGE2 minimizes any potential unwanted effects on the patient inclinicalsettings.InordertodeterminewhetherornotdmPGE2is aviabletherapyfortheexpansionofhumanHSCs,wearecurrently performingUCBTinthemouseusinghCBcells.Preliminaryresults indicatethattheexvivotreatmentofhCBcellswithdmPGE2and transplantationintoNOD/SCIDmiceisnotharmfultoeitherthe transplanted cells or to the recipient. Significantly, humanderived cellscanbedetectedinthebonemarrowat6weeksposttransplan tation (North, Goessling, and Zon, unpublished data). Ongoing studieswillestablishwhetherdmPGE2treatmentofhCBcellswill provide a significant enhancement of engraftment and longterm multilineagerepopulation.AhumanphaseIclinicaltrialscheduled for2008willmonitorpatientoutcometodeterminetheeffectsofex vivodmPGE2treatmentofoneunitofhCBcellsinadoublecord bloodsetting.

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