title: Upregulation of matrix metalloproteinase triggers transdifferentiation of retinal pigmented epithelial cells in Xenopus laevis: A Link between inflammatory response and regeneration.
abstract: In adult Xenopus eyes, when the whole retina is removed, retinal pigmented epithelial (RPE) cells become activated to be retinal stem cells and regenerate the whole retina. In the present study, using a tissue culture model, it was examined whether upregulation of matrix metalloproteinases (Mmps) triggers retinal regeneration. Soon after retinal removal, Xmmp9 and Xmmp18 were strongly upregulated in the tissues of the RPE and the choroid. In the culture, Mmp expression in the RPE cells corresponded with their migration from the choroid. A potent MMP inhibitor, 1,10-PNTL, suppressed RPE cell migration, proliferation, and formation of an epithelial structure in vitro. The mechanism involved in upregulation of Mmps was further investigated. After retinal removal, inflammatory cytokine genes, IL-1β and TNF-α, were upregulated both in vivo and in vitro. When the inflammation inhibitors dexamethasone or Withaferin A were applied in vitro, RPE cell migration was severely affected, suppressing transdifferentiation. These results demonstrate that Mmps play a pivotal role in retinal regeneration, and suggest that inflammatory cytokines trigger Mmp upregulation, indicating a direct link between the inflammatory reaction and retinal regeneration. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1086-1100, 2017.
authors.affiliation: Developmental Neurobiology Laboratory, Department of Biological Sciences, Nara Women's University, Nara, 630-8506, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Naitoh
authors.affiliation: Developmental Neurobiology Laboratory, Department of Biological Sciences, Nara Women's University, Nara, 630-8506, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Suganuma
authors.affiliation: Developmental Neurobiology Laboratory, Department of Biological Sciences, Nara Women's University, Nara, 630-8506, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Growth Regulation, Institute of Frontier Medical Sciences, Kyoto University, 606-8585, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Growth Regulation, Institute of Frontier Medical Sciences, Kyoto University, 606-8585, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hiramuki
authors.affiliation: Department of Growth Regulation, Institute of Frontier Medical Sciences, Kyoto University, 606-8585, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fujisawa-Sehara
authors.affiliation: Department of Biotechnology, Kyoto Institute of Technology, Kyoto, 606-8585, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
authors.affiliation: Developmental Neurobiology Laboratory, Department of Biological Sciences, Nara Women's University, Nara, 630-8506, Japan.|Unit of Neural Development and Regeneration, Department of Biology, Nara Medical University, Nara, 634-8521, Japan.
authors.forename: Masasuke
authors.identifier: 0000-0002-7835-9211
authors.initials: M
authors.lastname: Araki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects; D009924:Organ Culture Techniques; D010618:Phenanthrolines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012160:Retina / Q000166:cytology*; D055213:Retinal Pigment Epithelium / Q000502:physiology*; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D054358:Withanolides / Q000494:pharmacology / Q000633:toxicity; D014982:Xenopus laevis / Q000033:anatomy & histology*
chemical_list: D000893:Anti-Inflammatory Agents; D010618:Phenanthrolines; D011480:Protease Inhibitors; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D003907:Dexamethasone; D020782:Matrix Metalloproteinases; C009684:withaferin A; C025205:1,10-phenanthroline
keywords: matrix metalloproteinase; retinal pigmented epithelium; retinal regeneration; tissue inflammation; Xenopus laevis; transdifferentiation