Notch信号通路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成脂分化。

Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway.

作者信息

Song Bao-quan, Chi Ying, Li Xue, Du Wen-jing, Han Zhi-Bo, Tian Jian-jian, Li Juan-juan, Chen Fang, Wu He-he, Han Li-xin, Lu Shi-hong, Zheng Yi-zhou, Han Zhong-chao

机构信息

State Key Laboratory of Experimental Hematology, National Engineering Research Center of Stem Cells, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

出版信息

Cell Physiol Biochem. 2015;36(5):1991-2002. doi: 10.1159/000430167. Epub 2015 Jul 17.

DOI:10.1159/000430167

PMID:26202359

Abstract

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.

摘要

背景

Notch信号通路参与广泛的发育过程，包括细胞命运决定。本研究旨在确定Notch信号在人骨髓来源间充质干细胞（BM-MSCs）成脂分化中的作用。

方法

用γ-分泌酶抑制剂N-[N-(3,5-二氟苯乙酰基-L-丙氨酰)]-S-苯甘氨酸叔丁酯（DAPT）抑制Notch信号。然后分析涉及间充质干细胞成脂分化的标志物、相关通路PTEN-PI3K/Akt/mTOR以及自噬激活情况。此外，使用自噬抑制剂氯喹（CQ）和3-甲基腺嘌呤（3-MA）研究自噬在DAPT诱导的间充质干细胞成脂分化中的作用。

结果

我们首先证实了间充质干细胞向脂肪细胞分化过程中Notch基因表达下调，并表明抑制Notch信号显著增强了间充质干细胞的成脂分化。此外，Notch抑制剂DAPT通过作用于PTEN-PI3K/Akt/mTOR通路诱导早期自噬。自噬抑制剂CQ和3-MA显著消除了DAPT诱导的自噬和间充质干细胞成脂分化的作用。