title: Simvastatin modulates mesenchymal stromal cell proliferation and gene expression.
abstract: Statins are widely used hypocholesterolemic drugs that block the mevalonate pathway, responsible for the biosysnthesis of cholesterol. However, statins also have pleiotropic effects that interfere with several signaling pathways. Mesenchymal stromal cells (MSC) are a heterogeneous mixture of cells that can be isolated from a variety of tissues and are identified by the expression of a panel of surface markers and by their ability to differentiate in vitro into osteocytes, adipocytes and chondrocytes. MSC were isolated from amniotic membranes and bone marrows and characterized based on ISCT (International Society for Cell Therapy) minimal criteria. Simvastatin-treated cells and controls were directly assayed by CFSE (Carboxyfluorescein diacetate succinimidyl ester) staining to assess their cell proliferation and their RNA was used for microarray analyses and quantitative PCR (qPCR). These MSC were also evaluated for their ability to inhibit PBMC (peripheral blood mononuclear cells) proliferation. We show here that simvastatin negatively modulates MSC proliferation in a dose-dependent way and regulates the expression of proliferation-related genes. Importantly, we observed that simvastatin increased the percentage of a subset of smaller MSC, which also were actively proliferating. The association of MSC decreased size with increased pluripotency and the accumulating evidence that statins may prevent cellular senescence led us to hypothesize that simvastatin induces a smaller subpopulation that may have increased ability to maintain the entire pool of MSC and also to protect them from cellular senescence induced by long-term cultures/passages in vitro. These results may be important to better understand the pleiotropic effects of statins and its effects on the biology of cells with regenerative potential.
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Dalila Lucíola
authors: DL
authors: Zanette
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Julio Cesar Cetrulo
authors: JC
authors: Lorenzi
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Rodrigo Alexandre
authors: RA
authors: Panepucci
authors: Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Patricia Vianna Bonini
authors: PV
authors: Palma
authors: Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Daiane Fernanda
authors: DF
authors: Dos Santos
authors: Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Karen Lima
authors: KL
authors: Prata
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors: Wilson Araújo
authors: WA
authors: Silva
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin