In VitroandIn VivoEffects of Metformin on Osteopontin Expression in Mice Adipose-Derived Multipotent Stromal Cells and Adipose Tissue

Abstract

Metformin is applied not only as antidiabetic drug, but also in the treatment of obesity or as antiaging drug. The first part of the research discussed the effect of metformin at concentrations of 1 mM, 5 mM, and 10 mM on the morphology, ultrastructure, and proliferation potential of mice adipose-derived multipotent mesenchymal stromal cells (ASCs) in vitro. Additionally, we determined the influence of metformin on mice adipose tissue metabolism. This study has shown for the first time that metformin inhibits the proliferative potential of ASCs in vitro in a dose- and time-dependent manner. In addition, we have found a significant correlation between the activity of ASCs and osteopontin at the mRNA and protein level. Furthermore, we have demonstrated that 5 mM and 10 mM metformin have cytotoxic effect on ASCs, causing severe morphological, ultrastructural, and apoptotic changes. The reduced level of OPN in the adipose tissue of metformin-treated animals strongly correlated with the lower expression of Ki67 and CD105 and increased caspase-3. The metformin influenced also circulating levels of OPN, which is what was found with systemic and local action of metformin. The results are a valuable source of information regarding the in vitro effect of metformin on adipose-derived stem cells.

Metformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem CellsIn Vitro, and Increases Bone DensityIn Vivo

“…While commonly known as an antidiabetic drug, metformin is recognized not only as a hypoglycemic agent, but also as a potential geroprotector, a drug that protects against the aging process [ 34 ]. It has been previously demonstrated that metformin increases the lifespan of mice [ 2 ] and enhances the viability and proliferative activity of mesenchymal stromal stem cells [ 35 ]. Thus, its application as an antiaging drug in part follows the hypothesis that “we are as old as our adult stem cells are.” The antiaging effects of metformin are most likely explained by the upregulation of circulating insulin-like growth factor-1 (IGF-1) in peripheral blood that has been recognized as a crucial factor in the context of longevity [ 36 ].…”

Metformin Increases Proliferative Activity and Viability of Multipotent Stromal Stem Cells Isolated from Adipose Tissue Derived from Horses with Equine Metabolic Syndrome

“…Adipose tissue is defined by heterogenous cellular composition that may be altered during disease conditions, such as diabetes and equine metabolic syndrome [46,47,48,49]. The morphology of mature adipocytes is also influenced by physiological conditions and might change under specific medication treatment, e.g., metformin was shown to reduce the diameter of adipocytes as well as to induce a greater heterogeneity of the tissue [50]. Currently, much attention is paid to the cellular composition of stromal vascular fraction (SVF) obtained from adipose tissue.…”

“…Earlier, the pro-proliferative effect of metformin was also established in terms of MSCs derived from bone marrow (BMSC) and osteoblast progenitors [58,59], as well as adipose-derived stromal cells [60]. Metformin generally acts in dose- and time-dependent manner, therefore, consideration of proper metformin dosage is crucial in terms of obtaining a desirable effect [50,61]. Metformin is also known as an anticancer drug.…”

“…We previously tested metformin at concentrations that inhibited proliferation of various cancer cell lines, including breast, ovarian and pancreatic [62]. Our results showed that metformin in higher concentrations exerts an anti-proliferative effect towards mASCs [50] and mBMSCs [61].…”

Metformin Promotes Osteogenic Differentiation of Adipose-Derived Stromal Cells and Exerts Pro-Osteogenic Effect Stimulating Bone Regeneration

“…Additionally, our previous research showed that administration of metformin in mice may negatively influence ASCs’ proliferation and alter adipose tissue structure—the source of ASCs. Moreover, metformin, in a dose-dependent manner, inhibited the expression and production of osteopontin by mice ASCs [23]. In this context, the anti-proliferative effect of metformin may also be essential for modulation of ASCs osteogenic differentiation in vitro.…”