Department of Otolaryngology, the Second Affiliated Hospital of the Naval Military Medical University (Shanghai Changzheng Hospital), Shanghai, People's Republic of China.
School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China.
Theranostics. 2023 May 11;13(9):2896-2913. doi: 10.7150/thno.81153. eCollection 2023.
Gustation is important to several biological functions in mammals. However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function. This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function. We used both mice and taste organoid models to study the effect of cisplatin on taste buds. Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation. Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation. The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment. Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids. LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy. LY411575 treatment could offset the increased number of Pax1 or Pycr1 cells induced by cisplatin in the circumvallate papilla and taste organoids. This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients.
味觉对于哺乳动物的几个生物学功能很重要。然而，化疗药物常常会损害癌症患者的味觉感知，而对于大多数药物，其潜在机制仍不清楚，也没有有效的方法来恢复味觉功能。本研究探讨了顺铂对味觉细胞稳态和味觉功能的影响。我们使用小鼠和味觉类器官模型来研究顺铂对味蕾的影响。味觉计检测、味觉神经记录、RNA 测序、定量 PCR 和免疫组织化学分析用于分析顺铂诱导的味觉行为和功能、转录组、细胞凋亡、细胞增殖和味觉细胞生成的变化。顺铂抑制了味丘的增殖并促进了细胞凋亡，导致味觉功能和受体细胞生成显著受损。顺铂处理后，与细胞周期、代谢过程和炎症反应相关的基因的转录谱发生了显著改变。顺铂抑制了味觉类器官的生长，促进了细胞凋亡，推迟了味觉受体细胞的分化。γ-分泌酶抑制剂 LY411575 减少了凋亡细胞的数量，并增加了增殖细胞和味觉受体细胞的数量，这可能表明它是一种对抗化疗的味觉组织保护剂。LY411575 处理可以抵消顺铂在味丘和味觉类器官中诱导的 Pax1 或 Pycr1 细胞数量的增加。本研究强调了顺铂对味觉细胞稳态和功能的抑制作用，确定了化疗调节的关键基因和生物学过程，并提出了治疗癌症患者味觉功能障碍的潜在治疗靶点和策略。
