Konar Gregory, Flickinger Zachary, Sharma Shivani, Vallone Kyle, Lyon Charles, Doshier Claire, Lyon William, Patton James G
Department of Biological Sciences, Vanderbilt University, Nashville TN, USA.
bioRxiv. 2023 Jan 16:2023.01.16.524296. doi: 10.1101/2023.01.16.524296.
Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing proinflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after NMDA damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.
斑马鱼能够通过米勒胶质细胞的作用，在视网膜受损时自发地进行再生。尽管米勒胶质细胞（MG）在高等脊椎动物中是保守存在的，但视网膜损伤后的再生能力却丧失了。最近的研究工作聚焦于组织再生过程中的炎症调节，其中巨噬细胞和小胶质细胞发挥着精确的时间性作用。已退出细胞周期的衰老细胞大多与衰老相关，但它们仍具有代谢活性，作为衰老相关分泌表型（SASP）的一部分释放促炎信号分子。在此，我们发现，在视网膜受损后，一部分表达小胶质细胞/巨噬细胞标志物的细胞也表达衰老标志物。这些细胞在视网膜再生过程中呈现出出现和清除的时间模式。通过衰老细胞溶解疗法过早清除衰老细胞，会导致NMDA损伤后神经节细胞层的增殖减少和修复不完全。我们的研究结果表明，调节衰老细胞反应对于平衡炎症、再生、可塑性和修复，而非纤维化和瘢痕形成，具有重要作用。
