Abstract
Bone marrow-derived mesenchymal cells (BM-MSCs) are able to differentiate into adipocytes, which can secrete adipokines to affect BM-MSC proliferation and differentiation. Recent evidences indicated that adipocytes can secrete fatty acid metabolites, such as palmitic acid methyl ester (PAME), which is able to cause vasorelaxation and exerts anti-inflammatory effects. However, effects of PAME on BM-MSC proliferation remain unclear. The aim of this study was to investigate the effect of PAME on human BM-MSC (hBM-MSC) proliferation and its underlying molecular mechanisms. hBM-MSCs were treated with PAME for 48 h and then subjected to various analyses. The results from the present study show that PAME significantly reduced the levels of G2/M phase regulatory proteins, cyclin-dependent kinase 1 (Cdk1), and cyclin B1 and inhibited proliferation in hBM-MSCs. Moreover, the level of Mdm2 protein decreased, while the levels of p21 and p53 protein increased in the PAME-treated hBM-MSCs. However, PAME treatment did not significantly affect apoptosis/necrosis, ROS generation, and the level of Cdc25C protein. PAME also induced intracellular acidosis and increased intracellular Ca2+ levels. Cotreatment with PAME and Na+/H+ exchanger inhibitors together further reduced the intracellular pH but did not affect the PAME-induced decreases of cell proliferation and increases of the cell population at the G2/M phase. Cotreatment with PAME and a calcium chelator together inhibited the PAME-increased intracellular Ca2+ levels but did not affect the PAME-induced cell proliferation inhibition and G2/M cell cycle arrest. Moreover, the half-life of p53 protein was prolonged in the PAME-treated hBM-MSCs. Taken together, these results suggest that PAME induced p53 stabilization, which in turn increased the levels of p53/p21 proteins and decreased the levels of Cdk1/cyclin B1 proteins, thereby preventing the activation of Cdk1, and eventually caused cell cycle arrest at the G2/M phase. The findings from the present study might help get insight into the physiological roles of PAME in regulating hBM-MSC proliferation.
Highlights
Mesenchymal stem cells (MSCs), found in bone marrow stroma, adipose, and many other tissues, are candidates for tissue regeneration due to their high proliferation rate and potential for multilineage differentiation [1]
Our results show that the palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME) concentrations in the flushing medium are 44.44 μM and 30.87 μM, respectively (Figures 1(c) and 1(d)), and they are not statistically significantly different from the concentrations obtained from the flushing phosphate-buffered saline (PBS)
Our results show that PAME in the culture medium containing 1% or 3% fetal bovine serum (FBS) significantly inhibited human BM-MSC (hBM-MSC) proliferation, and PAME had the strongest inhibition in the medium containing 1% FBS (Supplement 1)
Summary
Mesenchymal stem cells (MSCs), found in bone marrow stroma, adipose, and many other tissues, are candidates for tissue regeneration due to their high proliferation rate and potential for multilineage differentiation [1]. Human bone marrow-derived MSCs (hBM-MSCs) have been studied extensively for many years and used in multiple clinical studies and trials. They are self-renewable and retain the potential to differentiate into pericytes, myofibroblasts, bone marrow stromal cells, osteocytes, osteoblasts, and endothelial cells, all of which support hematopoiesis and stable bone mass [4, 5]. Gender and age show significant effect on the number of hBM-MSCs and their proliferative capacity [6, 7]. The decrease in the number of resident MSCs may be one of the most important factors responsible for reduction in bone formation and the subsequent increase in bone fragility [8]
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