Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice.
Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice.
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DOI：
10.1016/j.exer.2011.09.020
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发表时间：
2011-12
影响因子：
3.4
通讯作者：
Scott, Edward W.
中科院分区：
文献类型：
--
作者：
Xia, Huiming;Krebs, Mark P.;Kaushal, Shalesh;Scott, Edward W.
关键词：
再生医学有望恢复在人类疾病中被破坏的细胞和组织，包括退行性眼病。然而，这种方法在眼睛中的发展受到缺乏显示眼组织稳健再生的动物模型的限制。在这里，我们测试了MRL/MpJ小鼠，表现出增强的伤口愈合，是否可以有效地再生视网膜色素上皮（RPE）后，模仿这种组织的损失，在年龄相关性黄斑变性的损伤。MRL/MpJ和对照AKR/J小鼠的RPE通过眶后注射20 mg/kg体重的碘酸钠而损伤，滴定研究表明这对于突出对损伤的反应中的品系差异是最佳的。以该剂量注射碘酸钠后5天，两种品系的视网膜电图显示与未处理小鼠相比显著降低的等效视网膜反应。在注射后1个月和2个月，MRL/MpJ小鼠的视网膜反应得到恢复，但AKR/J小鼠没有。眼杯冷冻切片的视野和荧光显微镜检查表明，在MRL/MpJ和AKR/J小鼠中，RPE细胞和RPE 65免疫染色的初始中心损失，外周RPE保留。鬼笔环肽染色的后眼整体证实了这种模式的RPE损失，并揭示了一个过渡区，其特征在于RPE细胞脱落和重组的两种菌株，表明类似的初始反应损伤。注射后1个月，MRL/MpJ小鼠的中央RPE细胞、RPE 65免疫染色和鬼笔环肽染色恢复，但AKR/J小鼠未恢复。在碘酸钠处理后给药1个月后，在MRL/MpJ小鼠的整个RPE中观察到BrdU掺入，但在AKR/J小鼠中未观察到BrdU掺入，这与RPE增殖一致。这些发现为MRL/MpJ小鼠损伤后RPE的戏剧性再生提供了证据，支持视网膜功能的完全恢复，这在哺乳动物眼睛中尚未观察到。这个模型应该被证明是有用的，了解分子机制，再生的基础，并确定因素，促进视网膜色素上皮再生的年龄相关性黄斑变性和相关疾病。
Regenerative medicine holds the promise of restoring cells and tissues that are destroyed in human disease, including degenerative eye disorders. However, development of this approach in the eye has been limited by a lack of animal models that show robust regeneration of ocular tissue. Here, we test whether MRL/MpJ mice, which exhibit enhanced wound healing, can efficiently regenerate the retinal pigment epithelium (RPE) after an injury that mimics the loss of this tissue in age-related macular degeneration. The RPE of MRL/MpJ and control AKR/J mice was injured by retro-orbital injection of sodium iodate at 20 mg/kg body weight, which titration studies indicated was optimal for highlighting strain differences in the response to injury. Five days after sodium iodate injection at this dose, electroretinography of both strains revealed equivalent retinal responses that were significantly reduced compared to untreated mice. At one and two months post-injection, retinal responses were restored in MRL/MpJ but not AKR/J mice. Brightfield and fluorescence microscopy of eyecup cryosections indicated an initial central loss of RPE cells and RPE65 immunostaining in MRL/MpJ and AKR/J mice, with preservation of peripheral RPE. Phalloidin staining of posterior eye wholemounts confirmed this pattern of RPE loss, and revealed a transition region characterized by RPE cell shedding and restructuring in both strains, suggesting a similar initial response to injury. At one month post-injection, central RPE cells, RPE65 immunostaining and phalloidin staining were restored in MRL/MpJ but not AKR/J mice. BrdU incorporation was observed throughout the RPE of MRL/MpJ but not AKR/J mice after one month of administration following sodium iodate treatment, consistent with RPE proliferation. These findings provide evidence for a dramatic regeneration of the RPE after injury in MRL/MpJ mice that supports full recovery of retinal function, which has not been observed previously in mammalian eyes. This model should prove useful for understanding molecular mechanisms that underlie regeneration, and for identifying factors that promote RPE regeneration in age-related macular degeneration and related diseases.
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