title: Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis.
abstract: Human endometrium undergoes cyclic regeneration involving stem/progenitor cells, but the role of resident endometrial mesenchymal stem cells (eMSC) as progenitors of endometrial stromal fibroblasts (eSF) has not been definitively demonstrated. In endometriosis, eSF display progesterone (P4) resistance with impaired decidualization in vivo and in vitro. To investigate eMSC as precursors of eSF and whether endometriosis P4 resistance is inherited from eMSC, we analyzed transcriptomes of eutopic endometrium eMSC and eSF isolated by fluorescence-activated cell sorting (FACS) from endometriosis (eMSCendo, eSFendo) and controls (eMSCcontrol, eSFcontrol) and their derived primary cultures. Differentially expressed lineage-associated genes (LG) of FACS-isolated eMSC and eSF were largely conserved in endometriosis. In culture, eSFcontrol maintained in vitro expression of a subset of eSF LG and decidualized in vitro with P4 The eMSCcontrol cultures differentiated in vitro to eSF lineage, down-regulating eMSC LG and up-regulating eSF LG, showing minimal transcriptome differences versus eSFcontrol cultures and decidualizing in vitro. Cultured eSFendo displayed less in vitro LG stability and did not decidualize in vitro. In vitro, eMSCendo differentiated to eSF lineage but showed more differentially expressed genes versus eSFendo cultures, and did not decidualize in vitro, demonstrating P4 resistance inherited from eMSCendo Compared to controls, cultures from tissue-derived eSFendo uniquely had a pro-inflammatory phenotype not present in eMSCendo differentiated to eSF in vitro, suggesting divergent niche effects for in vivo versus in vitro lineage differentiation. These findings substantiate eMSC as progenitors of eSF and reveal eSF in endometriosis as having P4 resistance inherited from eMSC and a pro-inflammatory phenotype acquired within the endometrial niche.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Fatima
authors.initials: F
authors.lastname: Barragan
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Irwin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Shaina
authors.initials: S
authors.lastname: Balayan
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Oregon National Primate Research Center/Oregon Health & Science University, Endocrine Technologies Support Core, Beaverton, Oregon.
authors.forename: David W
authors.initials: DW
authors.lastname: Erikson
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Siemens Healthcare Diagnostics, Berkeley, California.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Sahar
authors.initials: S
authors.lastname: Houshdaran
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Department of Obstetrics and Gynecology and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Terhi T
authors.initials: TT
authors.lastname: Piltonen
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Reproductive Endocrinology and Infertility Division, Women's Health, Naval Medical Center, Portsmouth, Virginia.
authors.forename: Trimble L B
authors.initials: TL
authors.lastname: Spitzer
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey.
authors.forename: Ashley
authors.initials: A
authors.lastname: George
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rabban
authors.affiliation: Department of Obstetrics and Gynecology, Stanford University, Stanford, California.
authors.forename: Camran
authors.initials: C
authors.lastname: Nezhat
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California Linda.Giudice@ucsf.edu.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Giudice
mesh_terms: D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004715:Endometriosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D055153:Stem Cell Niche / Q000235:genetics*; D059467:Transcriptome / Q000502:physiology; D014591:Uterine Diseases / Q000235:genetics*
chemical_list: D018836:Inflammation Mediators
keywords: differentiation; endometriosis; endometrium; fibroblasts; mesenchymal stem cells