Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
Department of Electrical Engineering, College of Electrical and Communication Engineering, Yuan Ze University, Taoyuan, Taiwan; Department of Otolaryngology, Far Eastern Memorial Hospital, Taipei, Taiwan.
Biomaterials. 2021 Apr;271:120738. doi: 10.1016/j.biomaterials.2021.120738. Epub 2021 Mar 2.
Olfactory dysfunction significantly impairs the life quality of patients but without effective treatments to date. The previous report has demonstrated that chitosan mediates the differentiation of olfactory receptor neurons (ORNs) through insulin-like growth factors and insulin-like growth factor binding protein-2 axis in an in vitro model. However, whether chitosan can further treat olfactory dysfunction in vivo remains unexplored. This study aims to evaluate the therapeutic effect of chitosan on a 3-methylindole-induced anosmic rat model. Intraperitoneal injection of 3-methylindole is performed to induce anosmia in rats. Experimental results demonstrate that the food-finding duration after chitosan treatment gradually decrease to around 80 s, and both the olfactory neuroepithelium (ON) thickness and mature ORNs (expressing olfactory marker protein) are significantly restored. Furthermore, proliferating cells (expressing bromodeoxyuridine) are mainly co-expressed with immature ORNs (expressing βIII tubulin) below the intermediate layer of the ON in the chitosan-treated group on day 28 following 3-methylindole treatment. Conversely, proliferating cells are scattered over the ON, and co-localized with immature ORNs and sustentacular cells (expressing keratin 18) in the sham group, and even immature ORNs go into apoptosis (expressing DNA fragmentation and cleaved caspase-3), possibly causing incomplete regeneration. Consequently, chitosan regenerates the ON by regulating olfactory neural homeostasis and reducing ORN apoptosis, and serves as a potential therapeutic intervention for olfactory dysfunction in the future.
嗅觉功能障碍显著降低了患者的生活质量，但目前仍缺乏有效的治疗方法。先前的报告表明，壳聚糖通过胰岛素样生长因子和胰岛素样生长因子结合蛋白-2 轴在体外模型中介导嗅觉受体神经元 (ORN) 的分化。然而，壳聚糖是否能进一步治疗体内的嗅觉功能障碍尚未可知。本研究旨在评估壳聚糖对 3-甲基吲哚诱导的嗅觉障碍大鼠模型的治疗效果。通过腹腔注射 3-甲基吲哚诱导大鼠嗅觉障碍。实验结果表明，壳聚糖治疗后大鼠的觅食时间逐渐减少到 80 秒左右，嗅神经上皮 (ON) 厚度和成熟 ORN (表达嗅觉标记蛋白) 均显著恢复。此外，在 3-甲基吲哚处理后第 28 天，壳聚糖处理组中 ON 的中间层下方，增殖细胞 (表达溴脱氧尿苷) 主要与不成熟的 ORN (表达 βIII 微管蛋白) 共表达。相反，增殖细胞散在 ON 中，与未成熟的 ORN 和支持细胞 (表达角蛋白 18) 在假手术组中共定位，甚至不成熟的 ORN 发生凋亡 (表达 DNA 片段化和 cleaved caspase-3)，可能导致不完全再生。因此，壳聚糖通过调节嗅神经内稳态和减少 ORN 凋亡来再生 ON，并可能成为未来治疗嗅觉功能障碍的潜在干预手段。
