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Mol. Ther., Apr 05 2024, S1525-0016(24)00222-3 | https://doi.org/10.1016/j.ymthe.2024.04.006 Identification of Memory Mechanism in Tissue Resident Stem Cells via ANGPTL4 Beyond Immune Cells upon Viral Antigen Exposure

Eun-kyung Min ^a,b,1, Soo-Rim Kim ^a,b,1, Choon-Mi Lee ^a,b, Kun-Hee Na ^a,c, Chan Hum Park ^d, Byung-Chul Oh ^e, YunJae Jung ^a,c,*, In-Sun Hong ^a,b,*

^aDepartment of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
^bDepartment of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
^cDepartment of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea.
^dDepartment of Otolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Republic of Korea.
^eDepartment of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, 21999, Republic of Korea.

¹These authors contributed equally
^*Corresponding authors: correspondence to YunJae Jung or In-Sun Hong

Abstract

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 in vitro and in vivo. 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 shRNA knockdown in vitro and knockout (KO) mice in vivo 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 (WT) mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 K.O mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-15)
연구진국내 연구진
분야 의약학 > 재생의학

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