Distinctmesenchymallineagesandnichespromoteepithelialself-renewalandmyofibrogenesisinthelungJarodA.Zepp1,4,5,WilliamJ.Zacharias1,4,DavidB.Frank2,4,ChristinaA.Cavanaugh1,4,SuZhou5,MichaelP.Morley1,4,andEdwardE.Morrisey1,3,4,5,6,*1DepartmentofMedicine,DivisionofPediatricCardiology,Children’sHospitalofPhiladelphia,Philadelphia,PA191042DepartmentofPediatrics,DivisionofPediatricCardiology,Children’sHospitalofPhiladelphia,Philadelphia,PA191043DepartmentofCellandDevelopmentalBiology,UniversityofPennsylvaniaPhiladelphia,PA19104,USA4PennCenterforPulmonaryBiology,UniversityofPennsylvaniaPhiladelphia,PA19104,USA5PennCardiovascularInstitute,UniversityofPennsylvaniaPhiladelphia,PA19104,USA6PennInstituteforRegenerativeMedicine,UniversityofPennsylvaniaPhiladelphia,PA19104,USAAbstractThelungisanarchitecturallycomplexorgancomprisedofaheterogeneousmixtureofvariousepithelialandmesenchymallineages.Wehaveusedsingle-cellRNA-sequencingandsignalinglineagereporterstogenerateaspatialandtranscriptionalmapofthelungmesenchyme.Wefindthateachmesenchymallineagehasadistinctspatialaddressandtranscriptionalprofileleadingtouniquenicheregulatoryfunctions.TheMesenchymalAlveolarNicheCellisWntresponsive,expressesPdgfrα,andiscriticalforalveolarepithelialcellgrowthandself-renewal.Incontrast,theAxin2+MyofibrogenicProgenitorcellpreferentiallygeneratespathologicallydeleteriousmyofibroblastsafterinjury.Analysisofthesecretomeandreceptomeofthealveolarnicherevealsfunctionalpathwaysthatmediategrowthandself-renewalofalveolartype2progenitorcellsincludingIL-6/Stat3,Bmp,andFgfsignaling.Thesestudiesdefinethecellularandmolecularframeworkoflungmesenchymalnichesandrevealthefunctionalimportanceofdevelopmentalpathwayspromotingself-renewalversuspathologicalresponsetotissueinjury.*Leadcontact-Addresscorrespondenceto:EdwardE.Morrisey,Ph.D.,UniversityofPennsylvania,TranslationalResearchCenter,Room11-124,3400CivicCenterBoulevard,Building421,Philadelphia,PA19104-5129,Phone:215-573-3010,FAX:215-573-2094,emorrise@mail.med.upen...
