Instituto de Fisiología y Biofísica Prof. Bernardo Houssay (IFIBIO-Houssay) UBA y Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.
J Comp Neurol. 2020 Aug;528(12):2000-2020. doi: 10.1002/cne.24869. Epub 2020 Feb 7.
Injured retinas in mammals do not regenerate and heal with loss of function. The adult retina of zebrafish self-repairs after damage by activating cell-intrinsic mechanisms, which are regulated by extrinsic signal interactions. Among relevant regulatory extrinsic systems, purinergic signaling regulates progenitor proliferation during retinogenesis and regeneration and glia proliferation in proliferative retinopathies. ATP-activated P2X7 (P2RX7) and adenosine (P1R) receptors are involved in the progression of almost all retinopathies leading to blindness. Here, we examined P2RX7 and P1R participation in the retina regenerative response induced by photoreceptor damage caused by a specific dose of CoCl . First, we found that treatment of uninjured retinas with a potent agonist of P2RX7 (BzATP) provoked photoreceptor damage and mitotic activation of multipotent progenitors. In CoCl -injured retinas, blockade of endogenous extracellular ATP activity on P2RX7 caused further neurodegeneration, Müller cell gliosis, progenitor proliferation, and microglia reactivity. P2RX7 inhibition in injured retinas also increased the expression of lin28a and tnfα genes, which are related to multipotent progenitor proliferation. Levels of hif1α, vegf3r, and vegfaa mRNA were enhanced by blockade of P2RX7 immediately after injury, indicating hypoxic like damage and endothelial cell growth and proliferation. Complete depletion of extracellular nucleotides with an apyrase treatment strongly potentiated cell death and progenitor proliferation induced with CoCl . Blockade of adenosine P1 and A receptors (A R) had deleterious effects and deregulated normal timing for progenitor and precursor cell proliferation following photoreceptor damage. ATP via P2RX7 and adenosine via A R are survival extracellular signals key for retina regeneration in zebrafish.
哺乳动物受损的视网膜无法再生，功能丧失。斑马鱼的成年视网膜在受到损伤后会通过激活内在机制进行自我修复，这些机制受到外在信号相互作用的调节。在相关的调节外在系统中，嘌呤能信号在视网膜发生和再生过程中调节祖细胞增殖，并在增殖性视网膜病变中调节神经胶质细胞增殖。ATP 激活的 P2X7（P2RX7）和腺苷（P1R）受体参与了几乎所有导致失明的视网膜病变的进展。在这里，我们研究了 P2RX7 和 P1R 在特定剂量 CoCl 引起的光感受器损伤诱导的视网膜再生反应中的参与情况。首先，我们发现，用 P2RX7 的一种有效激动剂（BzATP）处理未受伤的视网膜会引起光感受器损伤和多能祖细胞的有丝分裂激活。在 CoCl 损伤的视网膜中，内源性细胞外 ATP 对 P2RX7 的活性阻断会导致进一步的神经退行性变、Müller 胶质细胞胶质增生、祖细胞增殖和小胶质细胞反应性。在受伤的视网膜中抑制 P2RX7 也会增加 lin28a 和 tnfα 基因的表达，这些基因与多能祖细胞增殖有关。P2RX7 阻断后立即损伤会增强 hif1α、vegf3r 和 vegfaa mRNA 的表达，表明缺氧样损伤和内皮细胞生长和增殖。用 apyrase 处理完全耗尽细胞外核苷酸会强烈增强 CoCl 诱导的细胞死亡和祖细胞增殖。用腺苷 P1 和 A 受体（A R）阻断剂处理会产生有害影响，并使光感受器损伤后祖细胞和前体细胞增殖的正常时间失调。ATP 通过 P2RX7，腺苷通过 A R，是斑马鱼视网膜再生的关键存活细胞外信号。
