Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.
Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.
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作者：
Chen M;Rajapakse D;Fraczek M;Luo C;Forrester JV;Xu H
视网膜色素上皮(RPE)细胞是视网膜健康和稳态的中心细胞。RPE细胞功能障碍或死亡是许多与年龄相关的视网膜退行性疾病，特别是与年龄相关的黄斑变性的基础。在衰老过程中，RPE细胞的数量减少，这表明细胞的丢失与年龄有关。RPE细胞被认为是有丝分裂后的，它们如何在衰老过程中修复损伤仍然没有明确的定义。我们发现，在C57BL/6J小鼠中，RPE细胞在衰老过程中体积增大并形成多核。多核现象似乎不是由于细胞融合，而是由于细胞分裂不完全，即胞质分裂失败。有趣的是，多核RPE细胞的吞噬活性与单核RPE细胞的吞噬活性没有差别。此外，体外培养的RPE细胞暴露于光感受器外段(POS)，特别是氧化的POS，可剂量依赖性地促进多核形成，抑制细胞增殖。胞质分裂失败和增殖抑制都需要接触POS。暴露于POS还可诱导RPE细胞中的活性氧产生和DNA氧化。我们认为RPE细胞具有在体内增殖和修复单层缺陷的潜力。我们进一步提出，RPE细胞传统上被接受的“有丝分裂后”状态是由于POS介导的接触抑制的一种修改形式，当与POS失去接触时，RPE细胞从这种状态中释放出来。这在长期存在的孔源性视网膜脱离中表现为明显的RPE细胞增殖(增殖性玻璃体视网膜病变)，在正常老化过程中更隐蔽地表现为多核。年龄相关的氧化应激可能促进RPE细胞胞质分裂和多核的失败。
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.