title: Epithelial-to-Mesenchymal Transition Enhances the Cardioprotective Capacity of Human Amniotic Epithelial Cells.
abstract: The amniotic epithelium consists of cells exhibiting mature epithelial cell characteristics, but also varying degrees of stemness. We tested the hypothesis that induction of epithelial-to-mesenchymal transition (EMT) in amniotic epithelial cells (AECs) derived from human placenta enhances their capacity to support the ischemic myocardium. In response to incubation with transforming growth factor-β1 (TGF-β1) protein, AECs lost their cobblestone morphology and acquired a fibroblastoid shape, associated with downregulation of E-cadherin, upregulation of N-cadherin, Akt phosphorylation, and intracellular periostin translocation. EMT-AECs displayed greatly enhanced mobility and secreted gelatinase activity compared with naive AECs. The surface presentation of CD105 and CD73 decreased, and RNA microarray analysis mirrored the loss of epithelial characteristics and transcriptional profile. Unmodified AECs and EMT-AECs were then injected intramyocardially in fully immunocompetent mice after permanent LAD ligation, and heart function was followed by MRI as well as 2D speckle tracking echocardiography after 4 weeks. EMT-AEC-treated infarct hearts displayed better global systolic function and improved longitudinal strain rate in the area of interest. Although no signals of human cells were detectable by histology, infarct size was smaller in EMT-AEC-treated hearts, associated with fewer TUNEL-positive cells and upregulation of periostin, while blood vessel density was increased in both ACE- and EMT-AEC-treated hearts. We conclude that EMT enhances the cardioprotective effects of human AECs.
authors.affiliation: Berlin Brandenburg Center for Regenerative Therapies, Berlin, Germany.
authors.forename: Rajika
authors.initials: R
authors.lastname: Roy
authors.forename: Marian
authors.initials: M
authors.lastname: Kukucka
authors.forename: Daniel
authors.initials: D
authors.lastname: Messroghli
authors.forename: Désirée
authors.initials: D
authors.lastname: Kunkel
authors.forename: Andreja
authors.initials: A
authors.lastname: Brodarac
authors.forename: Kristin
authors.initials: K
authors.lastname: Klose
authors.forename: Sven
authors.initials: S
authors.lastname: Geißler
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Kang
authors.forename: Yeong-Hoon
authors.initials: YH
authors.lastname: Choi
authors.forename: Christof
authors.initials: C
authors.lastname: Stamm
mesh_terms: D000650:Amnion / Q000166:cytology*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D020011:Protective Agents / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014463:Ultrasonography
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D020011:Protective Agents; D053773:Transforming Growth Factor beta1; D018093:Gelatinases