title: High glucose-induced hyperosmolarity impacts proliferation, cytoskeleton remodeling and migration of human induced pluripotent stem cells via aquaporin-1.
abstract: OBJECTIVE
  Hyperglycemia leads to adaptive cell responses in part due to hyperosmolarity. In endothelial and epithelial cells, hyperosmolarity induces aquaporin-1 (AQP1) which plays a role in cytoskeletal remodeling, cell proliferation and migration. Whether such impairments also occur in human induced pluripotent stem cells (iPS) is not known. We therefore investigated whether high glucose-induced hyperosmolarity impacts proliferation, migration, expression of pluripotency markers and actin skeleton remodeling in iPS cells in an AQP1-dependent manner.
  
  
  RESULTS
  Human iPS cells were generated from skin fibroblasts by lentiviral transduction of four reprogramming factors (Oct4, Sox2, Klf4, c-Myc). After reprogramming, iPS cells were characterized by their adaptive responses to high glucose-induced hyperosmolarity by incubation with 5.5mmol/L glucose, high glucose (HG) at 30.5mM, or with the hyperosmolar control mannitol (HM). Exposure to either HG or HM increased the expression of AQP1. AQP1 co-immunoprecipitated with β-catenin. HG and HM induced the expression of β-catenin. Under these conditions, iPS cells showed increased ratios of F-actin to G-actin and formed increased tubing networks. Inhibition of AQP1 with small interfering RNA (siRNA) reverted the inducing effects of HG and HM.
  
  
  CONCLUSIONS
  High glucose enhances human iPS cell proliferation and cytoskeletal remodeling due to hyperosmolarity-induced upregulation of AQP1.
authors.affiliation: Heart Failure Research, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA; Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Madonna
authors.affiliation: Heart Failure Research, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA; Department of Internal Medicine, Division of Cardiology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.affiliation: Heart Failure Research, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA.
authors.forename: Harnath
authors.initials: H
authors.lastname: Shelat
authors.affiliation: Pharmahungary Group, Szeged, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy. Electronic address: rdecater@unich.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
keywords: Aquaporin-1; Cytoskeleton remodeling; Diabetes; Hyperglycemia; Hyperosmolarity; Induced pluripotent stem cell