Simvastatin Modulates Mesenchymal Stromal Cell Proliferation and Gene Expression

Author(s)

Zanette, Dalila Luciola ^{[1, 2, 3, 4]} ; Cetrulo Lorenzi, Julio Cesar ^{[1, 2, 3, 4]} ; Panepucci, Rodrigo Alexandre ^{[1, 2, 3, 4]} ; Bonini Palma, Patricia Vianna ^{[1, 2, 3]} ; dos Santos, Daiane Fernanda ^{[1, 2, 3]} ; Prata, Karen Lima ^{[1, 2, 3]} ; Silva, Jr., Wilson Arajo ^{[1, 2, 3, 4]}

Affiliation

^[1] Natl Inst Sci & Technol Stem Cell & Cell Therapy, Ribeirao Preto - Brazil

^[2] Reg Blood Ctr Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[3] Ctr Cell Based Therapy CEPID FAPESP, Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, BR-14049 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: PLoS One; v. 10, n. 4 APR 13 2015.
• Web of Science Citations: 11

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. (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC