Mature Peripheral RPE Cells Have an Intrinsic Capacity to Proliferate; A Potential Regulatory Mechanism for Age-Related Cell Loss

Abstract

BackgroundMammalian peripheral retinal pigmented epithelium (RPE) cells proliferate throughout life, while central cells are senescent. It is thought that some peripheral cells migrate centrally to correct age-related central RPE loss.Methodology/Principal FindingsWe ask whether this proliferative capacity is intrinsic to such cells and whether cells located centrally produce diffusible signals imposing senescence upon the former once migrated. We also ask whether there are regional differences in expression patterns of key genes involved in these features between the centre and the periphery in vivo and in vitro. Low density RPE cultures obtained from adult mice revealed significantly greater levels of proliferation when derived from peripheral compared to central tissue, but this significance declined with increasing culture density. Further, exposure to centrally conditioned media had no influence on proliferation in peripheral RPE cell cultures at the concentrations examined. Central cells expressed significantly higher levels of E-Cadherin revealing a tighter cell adhesion than in the peripheral regions. Fluorescence-labelled staining for E-Cadherin, F-actin and ZO-1 in vivo revealed different patterns with significantly increased expression on central RPE cells than those in the periphery or differences in junctional morphology. A range of other genes were investigated both in vivo and in vitro associated with RPE proliferation in order to identify gene expression differences between the centre and the periphery. Specifically, the cell cycle inhibitor p27Kip1 was significantly elevated in central senescent regions in vivo and mTOR, associated with RPE cell senescence, was significantly elevated in the centre in comparison to the periphery.ConclusionsThese data show that the proliferative capacity of peripheral RPE cells is intrinsic and cell-autonomous in adult mice. These differences between centre and periphery are reflected in distinct patterns in junctional markers. The regional proliferation differences may be inversely dependent to cell-cell contact.

Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation

“…Ranbp2 is implicated in arresting mitotic progression (26,58,59), a process that is critical to support the repair capacity of the RPE, presumably due to differences in regenerative capacity between the central and peripheral RPE (70). Hence, we examined also changes of the proliferative capacity of the RPE at different ages between RPE-cre::Ranbp2 ϩ/ϩ and RPE-cre::Ranbp2…”

“…It is thought that the central RPE becomes senescent due to hyperplastic senile changes first proposed by Duke-Elder and Perkins (87), whereas the peripheral RPE retains repair capacity due to its competency to reenter the cell cycle (70). Although the molecular bases for the proliferative capacity of peripheral RPE are unresolved, they may arise from emmetropization, a coordinated process of development and growth of various tissues of the eye by mechanisms not yet elucidated (70,88).…”

“…It is thought that the central RPE becomes senescent due to hyperplastic senile changes first proposed by Duke-Elder and Perkins (87), whereas the peripheral RPE retains repair capacity due to its competency to reenter the cell cycle (70). Although the molecular bases for the proliferative capacity of peripheral RPE are unresolved, they may arise from emmetropization, a coordinated process of development and growth of various tissues of the eye by mechanisms not yet elucidated (70,88). Interestingly, a recent study showed that down-regulation of Ran GTPase promotes cellular senescence possibly by decreasing competency of nucleocytoplasmic transport driven by Ran GTPase (89 ::RPE-cre::Ranbp2 Ϫ/Ϫ , whereas the secondary effects on deficits of the dark-adapted ERG of rod photoreceptors appeared first in this transgenic line.…”

Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

“…The RPE monolayer, formed in the early embryo, is a terminally differentiated cell sheet that develops with a center to periphery gradient such that only the peripheral cells retain low levels of proliferation, whereas the remainder remains nonproliferative throughout life [39,40]. However, in culture, their normal quiescence can be released, resulting in a re-entry into the cell cycle accompanied by proliferation.…”

Bowman lecture on the role of inflammation in degenerative disease of the eye

“…However, when isolated and cultured in vitro the RPE has strong proliferative potential, while recent studies have shown that, even in vivo, adult peripheral RPE cells can proliferate. 90 In some conditions, RPE cell proliferation can be observed usually in association with significant degrees of inflammation such as uveitis, or prolonged retinal detachment. With age however, slowly progressive RPE cell death is the more likely outcome, most probably in the form of apoptosis (reviewed in Williams et al 77 ).…”