Metformin potentiates immunosuppressant activity and adipogenic differentiation of human umbilical cord-mesenchymal stem cells
Adriana Bajetto, Alessandra Pattarozzi, Rodolfo Sirito, Federica Barbieri, Tullio Florio
Abstract
Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation leading to insulin resistance, characterized by increased pro-inflammatory cytokines produced by adipocytes and infiltrated immune cells, which contributes to metabolic syndrome. We investigated metformin’s differentiation and immunoregulatory properties of human umbilical cord-mesenchymal stem cells (UC-MSC), as cellular basis of its beneficial role in metabolic dysfunctions. Isolation, characterization and multilineage differentiation of UC-MSC were performed using standard protocols and flow-cytometry. Metformin effects on UC-MSC growth was assessed by colony formation and MTT assay, gene and protein expression by qRT-PCR, and western blot analysis. Proliferation of peripheral blood mononuclear cells (PBMCs) co-cultured with metformin-treated UC-MSC-conditioned media was evaluated by dye dilution assay. We show that metformin decreases proliferation and colony formation of UC-MSCs and enhances their adipogenic lineage commitment. Metformin (3 mM) increases PPARγ and downregulates FABP4 mRNA both in basal and in adipogenic culture conditions; however, the modulation of PPARγ expression is unrelated to the antiproliferative effects. Moreover, metformin inhibits UC-MSC inflammatory activity reducing the expression of IL-6, MCP-1, and COX-2. Conditioned media, collected from metformin-treated UC-MSCs, down-regulate CD3+ T lymphocyte growth in stimulated PBMCs and, in particular, reduce the CD8+ T cell population. These results indicate that metformin may favor new adipocyte formation and potentiate immune suppressive properties of UC-MSCs. Thus, adipose tissue regeneration and anti-inflammatory activity may represent possible mechanisms by which metformin exerts its positive effect on lipid metabolism.