Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway
Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway
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Notch 信号传导的抑制通过自噬激活和 PTEN-PI3K/AKT/mTOR 途径促进间充质干细胞的脂肪形成分化
DOI：
10.1159/000430167
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Han, Zhong-chao
中科院分区：
文献类型：
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作者：
Song, Bao-quan;Chi, Ying;Han, Zhong-chao
背景：Notch信号通路参与广泛的发育过程，包括细胞命运决定。本研究旨在探讨Notch信号在人骨髓间充质干细胞（BM-MSCs）成脂分化中的作用。方法：γ-分泌酶抑制剂N-[N-（3，5-二氟-苯乙酰基-L-丙氨酰）]-S-苯基甘氨酸叔丁酯（DAPT）抑制Notch信号传导。分析骨髓间充质干细胞成脂分化相关标志物、相关通路PTEN-PI 3 K/Akt/mTOR和自噬激活。应用自噬抑制剂氯喹（CQ）和3-甲基腺嘌呤（3-MA）研究自噬在DAPT诱导MSCs向脂肪细胞分化中的作用。结果如下：我们首先证实了Notch基因表达在MSC脂肪细胞分化过程中下调，并显示Notch信号传导的抑制显著增强了MSC的成脂分化。此外，Notch抑制剂DAPT通过作用于PTEN-PI 3 K/Akt/mTOR通路诱导早期自噬。自噬抑制剂CQ和3-MA可显著抑制DAPT诱导的MSCs自噬和成脂分化。结论：我们的研究结果表明，Notch信号的抑制可以促进骨髓间充质干细胞脂肪细胞的自噬介导的PTEN-PI 3 K/Akt/mTOR途径。Notch信号可能成为调控MSCs成脂分化的新靶点。
Background: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). Methods: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. Results: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. Conclusion: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.