Systemic administration of N-methyl-N-nitrosourea in rats resulted in the death of retinal photoreceptors followed by differentiation of retinal Muller glial cells into photoreceptor-like cells [27]. However, mammalian Muller glial cells exhibit an extremely limited proliferative capacity, which correlates with the expression of histone γH2AX and p21 protein. These proteins are known to be components of the cellular response to DNA damage [26]. The restriction of proliferation of human Muller glial cells prevents retinal replacement therapy by cell transplantation. On the other hand, the mechanism that limits the proliferation of Muller glia in the mammalian retina remains to be elucidated. We examined the Muller glial proliferative response and the DNA damage response in Muller glia in the postreplicative stage, as well as the expression of the p53 protein in response to the influence of retinotoxic N-methyl-N-nitrosourea. It was shown that N‑methyl-N-nitrosourea induced retinal degeneration in mice via apoptosis of photoreceptors, whereas the other retinal layers retained intact morphology. Nevertheless, the formation of DNA breaks and alkali-labile sites was observed in all retinal cells 5 h after the N-methyl-N-nitrosourea injection; these formations completely disappeared 15 h after N-methyl-N-nitrosourea injection. By 72 h, a significant increase in the number of DNA breaks in Muller glial cells was observed. The absence of bromodeoxyuridine incorporation into the retinal cells later testifies to the absence of proliferation of Muller glial cells and DNA repair synthesis. At the same time, an increased expression of the p53 protein, a universal marker of DNA damage, was observed in the retina. Thus, our findings support the concept of the “DNA damage response” with respect to Muller glial cells, according to which the DNA damage in Muller glial cell is related to the restricted proliferation of these cells in mice. Postreplicative repair is considered as a probable mechanism of the formation of DNA breaks in postreplicative Muller glial cells.

中文翻译：

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DNA 损伤和 p53 限制小鼠视网膜中 Müller 细胞的增殖以响应 N-甲基-N-亚硝基脲的影响

在大鼠中全身施用 N-甲基-N-亚硝基脲导致视网膜光感受器死亡，随后视网膜穆勒神经胶质细胞分化为光感受器样细胞 [27]。然而，哺乳动物穆勒神经胶质细胞的增殖能力极其有限，这与组蛋白 γH2AX 和 p21 蛋白的表达相关。已知这些蛋白质是对 DNA 损伤的细胞反应的组成部分 [26]。人穆勒神经胶质细胞增殖的限制阻止了通过细胞移植进行的视网膜替代疗法。另一方面，限制哺乳动物视网膜中穆勒神经胶质细胞增殖的机制仍有待阐明。我们检查了复制后阶段穆勒神经胶质细胞的增殖反应和 DNA 损伤反应，以及 p53 蛋白在视网膜毒性 N-甲基-N-亚硝基脲影响下的表达。结果表明，N-甲基-N-亚硝基脲通过光感受器的凋亡诱导小鼠视网膜变性，而其他视网膜层保持完整的形态。然而，在注射 N-甲基-N-亚硝基脲后 5 小时，在所有视网膜细胞中均观察到 DNA 断裂和碱不稳定位点的形成；这些地层在 N-甲基-N-亚硝基脲注射后 15 小时完全消失。到 72 小时，观察到穆勒神经胶质细胞中 DNA 断裂的数量显着增加。没有溴脱氧尿苷掺入视网膜细胞后来证明没有穆勒神经胶质细胞的增殖和 DNA 修复合成。同时，p53 蛋白的表达增加，在视网膜中观察到 DNA 损伤的通用标志物。因此，我们的研究结果支持关于穆勒神经胶质细胞的“DNA 损伤反应”的概念，根据该概念，穆勒神经胶质细胞的 DNA 损伤与小鼠中这些细胞的增殖受限有关。复制后修复被认为是在复制后的穆勒神经胶质细胞中形成 DNA 断裂的可能机制。