Cholesterol Retards Senescence in Bone Marrow Mesenchymal Stem Cells by Modulating Autophagy and ROS/p53/p21Cip1/Waf1 Pathway.

Yue Du,You Shu,Wei Zhao,Ming Gao,Jiaqi Liu,Yanjie Lu,Ti Yang,Guiye Zhang,Mingyu Zhang,Ruixue Liu,Zhuoyun Li,Shenjian Luo,Yue Zhang,Yu Zhang,Renzhong Lu

doi:10.1155/2016/7524308

Abstract

In the present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) of the 3rd passage displayed the senescence-associated phenotypes characterized with increased activity of SA-β-gal, altered autophagy, and increased G1 cell cycle arrest, ROS production, and expression of p53 and p21Cip1/Waf1 compared with BMSCs of the 1st passage. Cholesterol (CH) reduced the number of SA-β-gal positive cells in a dose-dependent manner in aging BMSCs induced by H2O2 and the 3rd passage BMSCs. Moreover, CH inhibited the production of ROS and expression of p53 and p21Cip1/Waf1 in both cellular senescence models and decreased the percentage of BMSCs in G1 cell cycle in the 3rd passage BMSCs. CH prevented the increase in SA-β-gal positive cells induced by RITA (reactivation of p53 and induction of tumor cell apoptosis, a p53 activator) or 3-MA (3-methyladenine, an autophagy inhibitor). Our results indicate that CH not only is a structural component of cell membrane but also functionally contributes to regulating cellular senescence by modulating cell cycle, autophagy, and the ROS/p53/p21Cip1/Waf1 signaling pathway.

Highlights

Cholesterol (CH) is essential for normal cellular function because it is a main structural component of the cell membrane and because it is involved in many functional processes via regulating cellular signaling pathways, such as cell proliferation, differentiation, and death [1]
The number of SA-β-gal positive cells was significantly decreased in the bone marrow mesenchymal stem cells (BMSCs) treated with 10 and 15 μg/mL CH compared with the control group (P < 0.01; Figures 2(a) and 2(b))
We demonstrated that CH possessed significant antisenescence property in aging BMSCs at the 3rd passage or under oxidative stress and the beneficial actions were likely conferred by the ability of CH to suppress the Reactive oxygen species (ROS)/p53/p21Cip1/Waf1 pathway and to regulate the autophagy process

Summary

Introduction

Cholesterol (CH) is essential for normal cellular function because it is a main structural component of the cell membrane and because it is involved in many functional processes via regulating cellular signaling pathways, such as cell proliferation, differentiation, and death [1]. It is plausible that delaying cell senescence can enhance viability and cellular function of BMSCs. We investigated whether CH could affect senescence process of BMSCs. Our study revealed that CH elicited significant antisenescence effects in aging BMSCs at the 3rd passage or induced by H2O2 [16], likely through suppressing the ROS/p53/p21Cip1/Waf signaling pathway and regulating autophagy process. Our study revealed that CH elicited significant antisenescence effects in aging BMSCs at the 3rd passage or induced by H2O2 [16], likely through suppressing the ROS/p53/p21Cip1/Waf signaling pathway and regulating autophagy process

Materials and Methods

Results

Discussion