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Induction of Fibroblast Senescence During Mouse Corneal Wound Healing
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
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2019 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 60, no 10, p. 3669-3679Article in journal (Refereed) Published
Abstract [en]

PURPOSE. To investigate the presence and role of fibroblast senescence in the dynamic process of corneal wound healing involving stromal cell apoptosis, proliferation, and differentiation.

METHODS. An in vivo corneal wound healing model was performed using epithelial debridement in C57BL/6 mice. The corneas were stained using TUNEL, Ki67, and alpha-smooth muscle actin (alpha-SMA) as markers of apoptosis, proliferation, and myofibroblastic differentiation, respectively. Cellular senescence was confirmed by senescence-associated beta-galactosidase (SA-beta-gal) staining and P16(Ink4a) expression. Mitogenic response and gene expression were compared among normal fibroblasts, H2O2-induced senescent fibroblasts, and TGF-beta-induced myofibroblasts in vitro. The senescence was further detected in mouse models of corneal scarring, alkali burn, and penetrating keratoplasty (PKP).

RESULTS. The apoptosis and proliferation of corneal stromal cells were found to peak at 4 and 24 hours after epithelial debridement. Positive staining of SA-beta-gal was observed clearly in the anterior stromal cells at 3 to 5 days. The senescent cells displayed P16(Ink4a) thorn vimentin+ alpha-SMA+, representing the major origin of activated corneal resident fibroblasts. Compared with normal fibroblasts and TGF-beta-induced myofibroblasts, H2O2-induced senescent fibroblasts showed a nonfibrogenic phenotype, including a reduced response to growth factor basic fibroblast growth factor (bFGF) or platelet-derived growth factor-BB (PDGF-BB), increased matrix metalloproteinase (MMP) 1/3/13 expression, and decreased fibronectin and collagen I expression. Moreover, cellular senescence was commonly found in the mouse corneal scarring, alkali burn, and PKP models.

CONCLUSIONS. Corneal epithelial debridement induced the senescence of corneal fibroblasts after apoptosis and proliferation. The senescent cells displayed a nonfibrogenic phenotype and may be involved in the self-limitation of corneal fibrosis.

Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC , 2019. Vol. 60, no 10, p. 3669-3679
Keywords [en]
corneal wound healing, senescence, apoptosis, proliferation, nonfibrogenic, SMOULIERE A, 1995, AMERICAN JOURNAL OF PATHOLOGY, V146, P56 gunawela Romesh I., 2011, JOURNAL OF REFRACTIVE SURGERY, V27, P111 ng Lingling, 2019, STEM CELLS TRANSLATIONAL MEDICINE, V8, P46 tthaei Mario, 2014, EXPERIMENTAL EYE RESEARCH, V129, P13 ao Xiaowen, 2016, BMC OPHTHALMOLOGY, V16, lson Steven E., 2007, EXPERIMENTAL EYE RESEARCH, V85, P305 mura T, 2006, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, V47, P1387 e Wen, 2007, NATURE, V445, P656 ilds Bennett G., 2016, SCIENCE, V354, P472 llego-Munoz Patricia, 2017, CYTOKINE, V96, P94 heredge LaTia, 2009, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, V50, P3128 vak JM, 2002, PROGRESS IN RETINAL AND EYE RESEARCH, V21, P1 e-Won K, 2015, Nature, V4, P547 ar Marjolein P., 2017, CELL, V169, P132 mpisi Judith, 2007, NATURE REVIEWS MOLECULAR CELL BIOLOGY, V8, P729 n Deursen Jan M., 2014, NATURE, V509, P439 yer Kathleen, 2016, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, V67, P2018
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-164543DOI: 10.1167/iovs.19-26983ISI: 000483885400008PubMedID: 31469894OAI: oai:DiVA.org:umu-164543DiVA, id: diva2:1370159
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2019-11-14Bibliographically approved

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