Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both and . Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown and knockout (KO) mice highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

中文翻译：

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通过 ANGPTL4 识别病毒抗原暴露后免疫细胞之外的组织驻留干细胞的记忆机制

尽管免疫细胞的记忆功能已明确，其特征是在初次接触病原体后对后续感染的抵抗力增强，但仍不清楚非免疫细胞，特别是组织驻留干细胞是否表现出类似的记忆机制。本研究表明，初始病毒抗原暴露（人乳头瘤病毒 [HPV]）对多种干细胞功能的不利影响在随后的二次暴露和 后显着加剧。重要的是，子宫内膜干细胞在连续暴露于HPV抗原后表现出强大的记忆功能，而完全分化的细胞（例如成纤维细胞和囊泡细胞）在对相同抗原暴露的反应中没有表现出相应的变化。通过小发夹 RNA 敲低和基因敲除 (KO) 小鼠实现血管生成素样 4 (ANGPTL4) 缺乏，突显了 ANGPTL4 在控制与各种干细胞过程相关的记忆功能中的关键作用。这种调节是通过组蛋白 H3 甲基化改变和 PI3K/Akt 信号通路响应连续 HPV 抗原暴露而发生的。此外，在连续暴露于HPV抗原后，野生型小鼠中明显的与各种干细胞功能相关的记忆功能在ANGPTL4 KO小鼠中没有观察到。总之，我们的研究结果强烈支持非免疫细胞，特别是组织驻留干细胞中存在记忆机制。