title: Endometrial Stromal Decidualization Responds Reversibly to Hormone Stimulation and Withdrawal.
abstract: Human endometrial stromal decidualization is required for embryo receptivity, angiogenesis, and placentation. Previous studies from our laboratories established that connexin (Cx)-43 critically regulates endometrial stromal cell (ESC) differentiation, whereas gap junction blockade prevents it. The current study evaluated the plasticity of ESC morphology and Cx43 expression, as well as other biochemical markers of cell differentiation, in response to decidualizing hormones. Primary human ESC cultures were exposed to 10 nM estradiol, 100 nM progesterone, and 0.5 mM cAMP for up to 14 days, followed by hormone withdrawal for 14 days, mimicking a biphasic ovulatory cycle. Reversible differentiation was documented by characteristic changes in cell shape. Cx43 was reversibly up- and down-regulated after the estradiol, progesterone, and cAMP treatment and withdrawal, respectively, paralleled by fluctuations in prolactin, vascular endothelial growth factor, IL-11, and glycodelin secretion. Markers of mesenchymal-epithelial transition (MET), and its counterpart epithelial-mesenchymal transition, followed reciprocal patterns corresponding to the morphological changes. Incubation in the presence of 18α-glycyrrhetinic acid, an inhibitor of gap junctions, partially reversed the expression of decidualization and MET markers. In the absence of hormones, Cx43 overexpression promoted increases in vascular endothelial growth factor and IL-11 secretion, up-regulated MET markers, and reduced N-cadherin, an epithelial-mesenchymal transition marker. The combined results support the hypothesis that Cx43-containing gap junctions and endocrine factors cooperate to regulate selected biomarkers of stromal decidualization and MET and suggest roles for both phenomena in endometrial preparation for embryonic receptivity.
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Berga
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Johnston-MacAnanny
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Neil
authors.initials: N
authors.lastname: Sidell
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.affiliation: Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D003656:Decidua / Q000187:drug effects / Q000378:metabolism*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018031:Connexin 43; C119129:18alpha-glycyrrhetinic acid; D006034:Glycyrrhetinic Acid