Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China.
Int J Mol Med. 2025 Jan;55(1). doi: 10.3892/ijmm.2024.5445. Epub 2024 Oct 25.
Cell senescence impedes the self‑renewal and osteogenic capacity of bone marrow mesenchymal stem cells (BMSCs), thus limiting their application in tissue regeneration. The present study aimed to elucidate the role and mechanism of repetitive element (RE) activation in BMSC senescence and osteogenesis, as well as the intervention effect of quercetin. In an H2O2‑induced BMSC senescence model, quercetin treatment alleviated senescence as shown by a decrease in senescence‑associated β‑galactosidase (SA‑β‑gal)‑positive cell ratio, increased colony formation ability and decreased mRNA expression of p21 and senescence‑associated secretory phenotype genes. DNA damage response marker γ‑H2AX increased in senescent BMSCs, while expression of epigenetic markers methylation histone H3 Lys9, heterochromatin protein 1α and heterochromatin‑related nuclear membrane protein lamina‑associated polypeptide 2 decreased. Quercetin rescued these alterations, indicating its ability to ameliorate senescence by stabilizing heterochromatin structure where REs are primarily suppressed. Transcriptional activation of REs accompanied by accumulation of cytoplasmic double‑stranded (ds)RNA, as well as triggering of the RNA sensor retinoic acid‑inducible gene I (RIG‑I) receptor pathway in H2O2‑induced senescent BMSCs were shown. Similarly, quercetin treatment inhibited these responses. Additionally, RIG‑I knockdown led to a decreased number of SA‑β‑gal‑positive cells, confirming its functional impact on senescence. Induction of senescence or administration of dsRNA analogue significantly hindered the osteogenic capacity of BMSCs, while quercetin treatment or RIG‑I knockdown reversed the decline in osteogenic function. The findings of the current study demonstrated that quercetin inhibited the activation of REs and the RIG‑I RNA sensing pathway via epigenetic regulation, thereby alleviating the senescence of BMSCs and promoting osteogenesis.
细胞衰老会阻碍骨髓间充质干细胞（BMSCs）的自我更新和成骨能力，从而限制其在组织再生中的应用。本研究旨在阐明重复元件（RE）在 BMSC 衰老和成骨中的作用和机制，以及槲皮素的干预效果。在 H2O2 诱导的 BMSC 衰老模型中，槲皮素处理减轻了衰老，表现为衰老相关β-半乳糖苷酶（SA-β-半乳糖）阳性细胞比例降低、集落形成能力增加和衰老相关分泌表型基因的 mRNA 表达降低。衰老的 BMSCs 中 DNA 损伤反应标志物 γ-H2AX 增加，而表观遗传标记物甲基化组蛋白 H3 Lys9、异染色质蛋白 1α 和异染色质相关核膜蛋白核纤层相关多肽 2 的表达降低。槲皮素挽救了这些改变，表明其通过稳定异染色质结构来改善衰老，RE 主要受到异染色质结构的抑制。RE 的转录激活伴随着细胞质双链（ds）RNA 的积累，以及 H2O2 诱导的衰老 BMSCs 中 RNA 传感器视黄酸诱导基因 I（RIG-I）受体途径的触发。同样，槲皮素处理抑制了这些反应。此外，RIG-I 敲低导致 SA-β-半乳糖阳性细胞数量减少，证实了其对衰老的功能影响。衰老的诱导或 dsRNA 类似物的给药显著阻碍了 BMSCs 的成骨能力，而槲皮素处理或 RIG-I 敲低逆转了成骨功能的下降。本研究的结果表明，槲皮素通过表观遗传调控抑制 RE 的激活和 RIG-I RNA 传感途径，从而减轻 BMSCs 的衰老并促进成骨。
