title: Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.
abstract: Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age-related retinal degenerative disorders particularly age-related macular degeneration. During aging RPE cells decline in number, suggesting an age-dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose-dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted 'postmitotic' status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long-standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age-related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7 BL, UK.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7 BL, UK.
authors.forename: Dinusha
authors.initials: D
authors.lastname: Rajapakse
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Science, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Fraczek
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7 BL, UK.
authors.forename: Chang
authors.initials: C
authors.lastname: Luo
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Science, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.|Ocular Immunology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, 6009, Australia.|Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, 6009, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7 BL, UK.
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D006706:Homeostasis; D006801:Humans; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010587:Phagocytosis; D010786:Photoreceptor Cells / Q000378:metabolism; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D014404:Tubulin / Q000378:metabolism; D014945:Wound Healing
chemical_list: D014404:Tubulin; D001973:Bromodeoxyuridine
keywords: aging; cytokinesis; multinucleation; phagocytosis; photoreceptor outer segments; retinal pigment epithelium