Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

Abstract

Because adipose-derived stem cells (ASCs) are usually expanded to acquire large numbers of cells for therapeutic applications, it is important to increase the production yield and regenerative potential during expansion. Therefore, a tremendous need exists for alternative ASC stimuli during cultivation to increase the proliferation and adipogenic differentiation of ASCs. The present study primarily investigated the involvement of megestrol acetate (MA), a progesterone analog, in the stimulation of ASCs, and identifies the target receptors underlying stimulation. Mitogenic and adipogenic effects of MA were investigated in vitro, and pharmacological inhibition and small interfering (si) RNA techniques were used to identify the molecular mechanisms involved in the MA-induced stimulation of ASCs. MA significantly increased the proliferation, migration, and adipogenic differentiation of ASCs in a dose-dependent manner. Glucocorticoid receptor (GR) is highly expressed compared with other nuclear receptors in ASCs, and this receptor is phosphorylated after MA treatment. MA also upregulated genes downstream of GR in ASCs, including ANGPTL4, DUSP1, ERRF11, FKBP5, GLUL, and TSC22D3. RU486, a pharmacological inhibitor of GR, and transfection of siGR significantly attenuated MA-induced proliferation, migration, and adipogenic differentiation of ASCs. Although the adipogenic differentiation potential of MA was inferior to that of dexamethasone, MA had mitogenic effects in ASCs. Collectively, these results indicate that MA increases the proliferation, migration, and adipogenic differentiation of ASCs via GR phosphorylation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:789-799 SIGNIFICANCEMagestrol acetate (MA) increases the proliferation, migration, and adipogenic differentiation of adipose-derived stem cells (ASCs) via glucocorticoid receptor phosphorylation. Therefore, MA can be applied to increase the production yield during expansion and can be used to facilitate adipogenic differentiation of ASCs.

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor

“…In contrast, adipose-derived stem cells (ASCs) are easily obtainable and expandable to provide sufficient numbers for therapeutic applications. Megestrol acetate (MA) imparts mitogenic effects on ASCs and increases the proliferation of ASCs via GR phosphorylation [177]. Future studies should compare in vitro results with in vivo preclinical findings and establish stem cell banks based on the heterogeneity of MSC subpopulations.…”

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells

“…ASCs were positive for CD44, CD73, CD90, CD105, human leukocyte antigen-I (HLA-I), and podocalyxin (PODXL), but were negative for hematopoietic markers such as CD34 and CD45 [ 32 , 33 ]. Multipotent differentiation potential was examined as described previously [ 34 , 35 ], and ASCs could be differentiated into adipocytes, osteocytes, and chondrocytes. We purchased human DP cells from PromoCell (#C-12071, PromoCell, Logan, Heidelberg, Germany).…”

Patient-Specific Age: The Other Side of the Coin in Advanced Mesenchymal Stem Cell Therapy

“…Female MSC showed a higher resistance in endotoxic and hypoxic injury models, inferring that improved survival in adverse micro-environments may be dependent on sex steroids. Indeed estrogen and estradiol exert a protective activity against apoptosis, favor proliferation, and delay the onset of senescence (Huang et al, 2013 ; Li et al, 2014c ; Sung et al, 2015 ).…”