Cdk4 Regulates Recruitment of Quiescent β-Cells and Ductal Epithelial Progenitors to Reconstitute β-Cell Mass 英文参考文献.docVIP

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Cdk4 Regulates Recruitment of Quiescent β-Cells and Ductal Epithelial Progenitors to Reconstitute β-Cell Mass 英文参考文献.doc

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Cdk4 Regulates Recruitment of Quiescent β-Cells and Ductal Epithelial Progenitors to Reconstitute β-Cell Mass 英文参考文献

Cdk4RegulatesRecruitmentofQuiescentb-Cellsand DuctalEpithelialProgenitorstoReconstituteb-CellMass Ji-HyeonLee1.,JunghyoJo2.,AnandwardhanA.Hardikar3,VipulPeriwal2,SushilG.Rane1* 1Regenerative Biology Section, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, UnitedStatesofAmerica,2LaboratoryofBiologicalModeling,NationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesofHealth,Bethesda, Maryland,UnitedStatesofAmerica,3StemCellsandDiabetesSection,NationalCentreforCellScience,Pune,Maharashtra,India Abstract Insulin-producing pancreatic islet b cells (b-cells) are destroyed, severely depleted or functionally impaired in diabetes. Therefore,replacingfunctionalb-cellmasswouldadvanceclinicaldiabetesmanagement.Wehavepreviouslydemonstrated the importance of Cdk4 in regulating b-cell mass. Cdk4-deficient mice display b-cell hypoplasia and develop diabetes, whereasb-cellhyperplasiaisobservedinmiceexpressinganactiveCdk4R24Ckinase.Whileb-cellreplicationappearstobe theprimarymechanismresponsibleforb-cellmassincrease,considerableevidencealsosupportsacontributionfromthe pancreaticductalepitheliumingenerationofnewb-cells.Further,whileitisbelievedthatmajorityofb-cellsareinastateof ‘dormancy’,itisunclearifandtowhatextentthequiescentcellscanbecoaxedtoparticipateinthe b-cellregenerative response.Here,weaddressthesequeriesusingamodelofpartialpancreatectomy(PX)inCdk4mutantmice.Toinvestigate the kinetics of the regeneration process precisely, we performed DNA analog-based lineage-tracing studies followed by mathematicalmodeling.WithinaweekafterPX,weobservedconsiderableproliferationofisletb-cellsandductalepithelial cells.Interestingly,themathematicalmodelshowedthatrecruitmentofquiescentcellsintotheactivecellcyclepromotesb- cellmassreconstitutionintheCdk4R24Cpancreas.Moreover,within24–48hourspost-PX,ductalepithelialcellsexpressing thetranscriptionfactorPdx-1dramaticallyincreased.W