Age-Dependent Decline in Mouse Lung Regeneration with Loss of Lung Fibroblast Clonogenicity and Increased Myofibroblastic Differentiation 英文参考文献.docVIP

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Age-Dependent Decline in Mouse Lung Regeneration with Loss of Lung Fibroblast Clonogenicity and Increased Myofibroblastic Differentiation 英文参考文献.doc

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Age-Dependent Decline in Mouse Lung Regeneration with Loss of Lung Fibroblast Clonogenicity and Increased Myofibroblastic Differentiation 英文参考文献

Age-DependentDeclineinMouseLungRegeneration withLossofLungFibroblastClonogenicityandIncreased MyofibroblasticDifferentiation JuliaA.Paxson1,AlishaGruntman1¤,ChristopherD.Parkin2,MelissaR.Mazan1,AirielDavis1,EdwardP. Ingenito3,AndrewM.Hoffman1* 1TuftsUniversityCummingsSchoolofVeterinaryMedicine,NorthGrafton,Massachusetts,UnitedStatesofAmerica,2CenterforNeuroscienceResearch,TuftsUniversity School of Medicine, Boston, Massachusetts, United States of America, 3Brigham and Women’s Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts,UnitedStatesofAmerica Abstract While aging leads to a reduction in the capacity for regeneration after pneumonectomy (PNX) in most mammals, this biologicalphenomenonhasnotbeencharacterizedoverthelifetimeofmice.Wemeasuredtheage-specific(3,9,24month) effectsofPNXonphysiology,morphometry,cellproliferationandapoptosis,globalgeneexpression,andlungfibroblast phenotype and clonogenicity in female C57BL6 mice. The data show that only 3 month old mice were fully capable of restoringlungvolumesbyday7andtotalalveolarsurfaceareaby21days.By9months,therateofregenerationwasslower (withincompleteregenerationby21days),andby24monthstherewasnoregrowth21dayspost-PNX.Theearlydeclinein regenerationratewasnotassociatedwithchangesinalveolarepithelialcelltypeII(AECII)proliferationorapoptosisrate. However,significantapoptosisandlackofcellproliferationwasevidentafterPNXinbothtotalcellsandAECIIcellsin24mo mice.Analysisofgeneexpressionatseveraltimepoints(1,3and7days)post-PNXin9versus3monthmicewasconsistent withamyofibroblastsignature(increasedTnc,Lox1,Col3A1,ElnandTnfrsf12a)andmorealphasmoothmuscleactin(aSMA) positive myofibroblasts were present after PNX in 9 month than 3 month mice. Isolated lung fibroblasts showed a significantage-dependentlossofclonogenicity.Moreover,lungfibroblastsisolatedfrom9and17monthmiceexhibited higheraSMA,Col3A1,Fn1andS100Aexpression,andlowerexpressionofthesurvivalgeneMdkconsistentwithterminal differentiation. These da