Preclinical Molecular Signatures of Spinal Cord Functional Restoration: Optimizing the Metamorphic Axolotl (Ambystoma mexicanum) Model in Regenerative Medicine
Preclinical Molecular Signatures of Spinal Cord Functional Restoration: Optimizing the Metamorphic Axolotl (Ambystoma mexicanum) Model in Regenerative Medicine
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DOI：
10.1089/omi.2020.0024
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发表时间：
2020-06-01
影响因子：
3.3
通讯作者：
Suzek, Baris Ethem
中科院分区：
文献类型：
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作者：
Demircan, Turan;Hacibektasogu, Harbiye;Suzek, Baris Ethem
再生医学为患有中枢和外周神经系统疾病的患者带来了希望。有尾目两栖动物如美西螈显示出特殊的再生能力，被认为是神经学和再生医学研究中重要的临床前模式生物。早期的研究表明，这种蝾螈的肢体再生能力显着下降与甲状腺激素诱导变态。变态蝾螈需要进一步验证作为临床前再生医学研究的阴性对照，更不用说其再生能力的分子底物的研究。在这项研究中，我们报告了新的观察实验诱导的变态对脊髓再生的蝾螈。令人惊讶的是，我们发现变性动物在实验诱导的损伤后成功地恢复了脊髓的功能。为了辨别脊髓再生的分子特征，我们在脊髓损伤（SCI）诱导（实验）和椎板切除术（假手术）组的损伤后1天和7天（dpi）进行转录组学分析。我们在1-和7-dpi分别观察到119和989个差异表达基因，而相应的小鼠直系同源基因在连接、免疫系统和细胞外基质相关途径中富集。总之，我们的研究结果挑战了先前的观念，有限的再生能力的变性蝾螈表现出成功的脊髓再生在我们的经验。此外，我们报告的分子签名，可以潜在地解释的机制基板的变性蝾螈的再生能力。据我们所知，这是第一份关于变性蝾螈对SCI的分子反应和功能恢复的报告。这些新发现推进了我们对脊髓再生的理解，从而可能有助于优化美西螈作为再生医学和综合生物学领域临床前模型的未来用途。
Regenerative medicine offers hope for patients with diseases of the central and peripheral nervous system. Urodele amphibians such as axolotl display an exceptional regenerative capacity and are considered as essential preclinical model organisms in neurology and regenerative medicine research. Earlier studies have suggested that the limb regeneration ability of this salamander notably decreases with induction of metamorphosis by thyroid hormones. Metamorphic axolotl requires further validation as a negative control in preclinical regenerative medicine research, not to mention the study of molecular substrates of its regenerative abilities. In this study, we report new observations on the effect of experimentally induced metamorphosis on spinal cord regeneration in axolotl. Surprisingly, we found that metamorphic animals were successful to functionally restore the spinal cord after an experimentally induced injury. To discern the molecular signatures of spinal cord regeneration, we performed transcriptomics analyses at 1- and 7-days postinjury (dpi) for both spinal cord injury (SCI)-induced (experimental) and laminectomy (sham) groups. We observed 119 and 989 differentially expressed genes at 1- and 7-dpi, respectively, while the corresponding mouse orthologous genes were enriched in junction-, immune system-, and extracellular matrix-related pathways. Taken together, our findings challenge the prior notions of limited regenerative ability of metamorphic axolotl which exhibited successful spinal cord regeneration in our experience. Moreover, we report on molecular signatures that can potentially explain the mechanistic substrates of the regenerative capacity of the metamorphic axolotl. To the best of our knowledge, this is the first report on molecular responses to SCI and functional restoration in metamorphic axolotls. These new findings advance our understanding of spinal cord regeneration, and may thus help optimize the future use of axolotl as a preclinical model in regenerative medicine and integrative biology fields.