Department of Biological Sciences, The Center for Stem Cells and Regenerative Medicine and The Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, IN, 46556, USA.
Department of Biological Sciences, The Center for Stem Cells and Regenerative Medicine and The Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, IN, 46556, USA.
Exp Eye Res. 2019 Jan;178:148-159. doi: 10.1016/j.exer.2018.09.015. Epub 2018 Sep 27.
Teleosts are unique in their ability to undergo persistent neurogenesis and to regenerate damaged and lost retinal neurons in adults. This contrasts with the human retina, which is incapable of replacing lost retinal neurons causing vision loss/blindness in the affected individuals. Two cell populations within the adult teleost retina generate new retinal neurons throughout life. Stem cells within the ciliary marginal zone give rise to all retinal cell types except for rod photoreceptors, which are produced by the resident Müller glia that are located within the inner nuclear layer of the entire retina. Understanding the mechanisms that regulate the generation of photoreceptors in the adult teleost retina may ultimately aid developing strategies to overcome vision loss in diseases such as retinitis pigmentosa. Here, we investigated whether photic deprivation alters the proliferative capacity of rod precursor cells, which are generated from Müller glia. In dark-adapted retinas, rod precursor cell proliferation increased, while the number of proliferating Müller glia and their derived olig2:EGFP-positive neuronal progenitor cells was not significantly changed. Cell death of rod photoreceptors was excluded as the inducer of rod precursor cell proliferation, as the number of TUNEL-positive cells and l-plastin-positive microglia in both the outer (ONL) and inner nuclear layer (INL) remained at a similar level throughout the dark-adaptation timecourse. Rod precursor cell proliferation in response to dark-adaptation was characterized by an increased number of EdU-positive cells, i.e. cells that were undergoing DNA replication. These proliferating rod precursor cells in dark-adapted zebrafish differentiated into rod photoreceptors at a comparable percentage and in a similar time frame as those maintained under standard light conditions suggesting that the cell cycle did not stall in dark-adapted retinas. Inhibition of IGF1-receptor signaling reduced the dark-adaptation-mediated proliferation response; however, caloric restriction which has been suggested to be integrated by the IGF1/growth hormone signaling axis did not influence rod precursor cell proliferation in dark-adapted retinas, as similar numbers were observed in starved and normal fed zebrafish. In summary, photic deprivation induces cell cycle entry of rod precursor cells via IGF1-receptor signaling independent of Müller glia proliferation.
硬骨鱼在持久神经发生和再生成年受损和丢失的视网膜神经元方面具有独特的能力。这与人类视网膜形成鲜明对比，人类视网膜无法替代丢失的视网膜神经元，从而导致受影响个体的视力丧失/失明。成年硬骨鱼视网膜内的两个细胞群终生产生新的视网膜神经元。睫状缘区的干细胞产生除杆状光感受器以外的所有视网膜细胞类型，而杆状光感受器是由位于整个视网膜内层核层的固有 Muller 胶质细胞产生的。了解调节成年硬骨鱼视网膜中光感受器生成的机制可能最终有助于开发克服诸如色素性视网膜炎等疾病导致的视力丧失的策略。在这里，我们研究了光剥夺是否会改变由 Muller 胶质细胞产生的杆状前体细胞的增殖能力。在暗适应的视网膜中，杆状前体细胞的增殖增加，而增殖的 Muller 胶质细胞及其衍生的 olig2:EGFP 阳性神经前体细胞的数量没有显著变化。杆状光感受器的细胞死亡被排除为杆状前体细胞增殖的诱导剂，因为在整个暗适应时间过程中，TUNEL 阳性细胞和 l-plastin 阳性小胶质细胞在外核层（ONL）和内核层（INL）中的数量保持相似水平。对暗适应的杆状前体细胞增殖的特征是 EdU 阳性细胞（即正在进行 DNA 复制的细胞）的数量增加。在暗适应的斑马鱼中，这些增殖的杆状前体细胞分化为杆状光感受器的比例和时间与在标准光照条件下维持的杆状光感受器相似，这表明细胞周期在暗适应的视网膜中没有停滞。IGF1 受体信号的抑制减少了暗适应介导的增殖反应；然而，热量限制（据推测通过 IGF1/生长激素信号轴整合）并没有影响暗适应的视网膜中的杆状前体细胞增殖，因为在饥饿和正常喂养的斑马鱼中观察到相似数量的杆状前体细胞。总之，光剥夺通过 IGF1 受体信号诱导杆状前体细胞进入细胞周期，而与 Muller 胶质细胞增殖无关。
