Department of Medicine, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand.
Biosci Rep. 2024 Oct 30;44(10). doi: 10.1042/BSR20240623.
Fisetin and quercetin, polyphenol flavonoids, have been shown to have a wide range of beneficial pharmacological effects including anti-inflammatory, antioxidative, and anti-cancer. Our previous work shows that fisetin also affects the specification of the adipogenic-osteogenic lineage of human mesenchymal stem cells (hMSCs) by modulating the Hippo-YAP signaling pathway. Although quercetin has a structure similar to that of fisetin, its effects on the functional properties of hMSCs have not yet been investigated. The objective of the present study is to determine the effects of quercetin on the various properties of hMSCs, including proliferation, migration, and differentiation capacity toward adipogenic and osteogenic lineages. The results show that while fisetin increases hMSC adipogenic differentiation, quercetin inhibited adipogenic differentiation of hMSCs. The inhibition is mediated, at least in part, by the activation of hippo signaling and up-regulation of miR-27b, which inhibits the expression of genes involved in all critical steps of lipid droplet biogenesis, resulting in a decrease in the number of lipid droplets in hMSCs. It is possible that the lack of hydroxylation of the 5 position on the A ring of quercetin could be responsible for its different effect on the adipogenic-osteogenic lineage specification of hMSCs compared with fisetin. Molecular docking and molecular dynamics simulation suggested that fisetin and quercetin possibly bind to serine / threonine protein kinases 4 (STK4/MST1), which is an upstream kinase responsible for LATS phosphorylation. Taken together, our results demonstrate more insight into the mechanism underlying the role of flavonoid fisetin and quercetin in the regulation of adipogenesis.
漆黄素和槲皮素是多酚类黄酮，具有广泛的有益的药理作用，包括抗炎、抗氧化和抗癌作用。我们之前的工作表明，漆黄素还通过调节 Hippo-YAP 信号通路影响人间充质干细胞（hMSCs）的成脂-成骨谱系特化。虽然槲皮素有与漆黄素相似的结构，但它对 hMSCs 功能特性的影响尚未被研究过。本研究的目的是确定槲皮素对 hMSCs 的各种特性的影响，包括增殖、迁移和向成脂和成骨谱系分化的能力。结果表明，虽然漆黄素增加 hMSC 的成脂分化，但槲皮素抑制 hMSCs 的成脂分化。这种抑制至少部分是由 hippo 信号的激活和 miR-27b 的上调介导的，miR-27b 抑制参与脂质滴生物发生所有关键步骤的基因的表达，导致 hMSCs 中的脂质滴数量减少。槲皮素 A 环 5 位缺乏羟化可能是其对 hMSCs 的成脂-成骨谱系特化作用与漆黄素不同的原因。分子对接和分子动力学模拟表明，漆黄素和槲皮素可能与丝氨酸/苏氨酸蛋白激酶 4（STK4/MST1）结合，STK4/MST1 是负责 LATS 磷酸化的上游激酶。总之，我们的结果更深入地了解了黄酮类化合物漆黄素和槲皮素在调节脂肪生成中的作用的机制。
