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

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.

Effects of Blue Light Emitting Diode Irradiation On the Proliferation, Apoptosis and Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells

“…It has been demonstrated that some specific proteins [31][32][33], miRNAs [34,35] and molecules [36][37][38] are involved in the regulation of osteogenic differentiation in BMSCs. These findings suggested that osteogenic differentiation is a complicated multifactorial process.…”

Strontium ranelate-induced anti-adipocytic effects are involved in negative regulation of autophagy in rat bone marrow mesenchymal stem cells

“…After 4 h of cell culture, the basal medium was replaced with fresh medium with or without SrRN (0.00, 0.05, 0.10, 0.50, 1.00, or 2.00 mM). The medium was replaced every two days, and the CCK-8 assay was implemented at different time-points (1,2,3,4,5,6, and 7 days). Briefly, to perform the assay the medium was replaced with 100 μL fresh medium, and the 10 μL CCK-8 reagent (Dojindo, Kumamoto, Japan) was added into each well.…”

“…Previous studies revealed complex effects of autophagy on adipocytic differentiation. On the one hand, the inhibition of autophagy might interfere with adipocytic differentiation [6,7], while on the other hand, autophagy might reduce lipid accumulation [13,14]. By adding an autophagy inhibitor and Akt selective antagonist to the induction and treatment group, respectively, we investigated the connection between autophagy and adipocytic differentiation, as well as the likely mechanism of SrRN associated with these processes.…”

“…Autophagy is also a complicated process which degrades intracellular components by formation of autophagosomes, which then fuse with lysosomes to form autolysosomes [5]. Growing evidence suggests that autophagy is implicated in lipid accumulation and adipocytic differentiation [6][7][8]. The Wnt/β-catenin pathway, and especially β-catenin, has been associated with the degradation effects of autophagy [9,10].…”

Bone Marrow Mesenchymal Stem Cell Transplantation Increases GAP-43 Expression via ERK1/2 and PI3K/Akt Pathways in Intracerebral Hemorrhage

“…Stem cell transplantation is one potential therapy effective for various nerve injuries [12]. Bone marrow mesenchymal stem cells (BMSCs) could differentiate into various cell types because they are multi-potent and have a self-renewing capacity [13].…”