Expression and Function of Cannabinoid Receptors CB1 and CB2 and Their Cognate Cannabinoid Ligands in Murine Embryonic Stem Cells 英文参考文献.docVIP

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Expression and Function of Cannabinoid Receptors CB1 and CB2 and Their Cognate Cannabinoid Ligands in Murine Embryonic Stem Cells 英文参考文献.doc

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Expression and Function of Cannabinoid Receptors CB1 and CB2 and Their Cognate Cannabinoid Ligands in Murine Embryonic Stem Cells 英文参考文献

ExpressionandFunctionofCannabinoidReceptorsCB1 andCB2andTheirCognateCannabinoidLigandsin MurineEmbryonicStemCells ShuxianJiang1,YigongFu1,JohnWilliams2,JodiAnneWood2,LakshmipathiPandarinathan2,ShiriAvraham1,AlexandrosMakriyannis2 ,Shalom Avraham1.,HavaKarsentyAvraham1. * 1DivisionofExperimentalMedicine,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica, 2CenterforDrugDiscovery,NortheasternUniversity,Boston,Massachusetts,UnitedStatesofAmerica Background.Characterizationofintrinsicandextrinsicfactorsregulatingtheself-renewal/divisionanddifferentiationofstem cellsiscrucialindeterminingembryonicstem(ES)cellfate.EScellsdifferentiateintomultiplehematopoieticlineagesduring embryoid body (EB) formation in vitro, which provides an experimental platform to define the molecular mechanisms controlling germ layer fate determination and tissue formation. Methods and Findings. The cannabinoid receptor type 1 (CB1)andcannabinoidreceptortype2(CB2)aremembersoftheG-proteincoupledreceptor(GPCR)family,thatareactivated byendogenousligands,theendocannabinoids.CB1receptorexpressionisabundantinbrainwhileCB2receptorsaremostly expressedinhematopoieticcells.However,theexpressionandthepreciserolesofCB1andCB2andtheircognateligandsinES cells are not known. We observed significant induction of CB1 and CB2 cannabinoid receptors during the hematopoietic differentiationofmurineES(mES)-derivedembryoidbodies.Furthermore,mEScellsaswellasES-derivedembryoidbodiesat days 7 and 14, expressed endocannabinoids, the ligands for both CB1 and CB2. The CB1 and CB2 antagonists (AM251 and AM630,respectively)inducedmEScelldeath,stronglysuggestingthatendocannabinoidsareinvolvedinthesurvivalofmES cells. Treatment of mES cells with the exogenous cannabinoid ligand D9-THC resulted in the increased hematopoietic differentiationofmEScells,whileadditionofAM251orAM630blockedembryoidbodyformationderivedfromthemEScells. Inaddition,cannabinoidagonistsinducedthechemotaxisofES-deri