Shimizu Yuki, Kiyooka Mariko, Ohshima Toshio
Functional Biomolecular Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Osaka, Japan.
DBT-AIST International Laboratory for Advanced Biomedicine, National Institute of Advanced Industrial Science and Technology, Osaka, Japan.
Front Cell Dev Biol. 2021 Apr 30;9:668408. doi: 10.3389/fcell.2021.668408. eCollection 2021.
Adult zebrafish have many neurogenic niches and a high capacity for central nervous system regeneration compared to mammals, including humans and rodents. The majority of radial glia (RG) in the zebrafish optic tectum are quiescent under physiological conditions; however, stab wound injury induces their proliferation and differentiation into newborn neurons. Although previous studies have functionally analyzed the molecular mechanisms of RG proliferation and differentiation and have performed single-cell transcriptomic analyses around the peak of RG proliferation, the cellular response and changes in global gene expression during the early stages of tectum regeneration remain poorly understood. In this study, we performed histological analyses which revealed an increase in isolectin B4+ macrophages prior to the induction of RG proliferation. Moreover, transcriptome and pathway analyses based on differentially expressed genes identified various enriched pathways, including apoptosis, the innate immune system, cell proliferation, cytokine signaling, p53 signaling, and IL6/Jak-Stat signaling. In particular, we found that Stat3 inhibition suppressed RG proliferation after stab wound injury and that IL6 administration into cerebroventricular fluid activates RG proliferation without causing injury. Together, the findings of these transcriptomic and functional analyses reveal that IL6/Stat3 signaling is an initial trigger of RG activation during optic tectum regeneration.
与包括人类和啮齿动物在内的哺乳动物相比，成年斑马鱼具有许多神经发生微环境，并且中枢神经系统再生能力很强。在生理条件下，斑马鱼视顶盖中的大多数放射状胶质细胞（RG）处于静止状态；然而，刺伤会诱导它们增殖并分化为新生神经元。尽管先前的研究已经从功能上分析了RG增殖和分化的分子机制，并在RG增殖高峰期进行了单细胞转录组分析，但对视顶盖再生早期阶段的细胞反应和全局基因表达变化仍知之甚少。在本研究中，我们进行了组织学分析，结果显示在诱导RG增殖之前，异凝集素B4+巨噬细胞增加。此外，基于差异表达基因的转录组和通路分析确定了各种富集通路，包括凋亡、先天免疫系统、细胞增殖、细胞因子信号传导、p53信号传导和IL6/Jak-Stat信号传导。特别是，我们发现抑制Stat3可抑制刺伤后RG的增殖，而向脑室注射IL6可激活RG增殖且不会造成损伤。总之，这些转录组和功能分析的结果表明，IL6/Stat3信号传导是视顶盖再生过程中RG激活的初始触发因素。
