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.

Osteogenic/Odontogenic Bioengineering with co-Administration of Simvastatin and Hydroxyapatite on Poly Caprolactone Based Nanofibrous Scaffold

“…29 Statins are a group of widely used lipid lowering drugs that block the biosynthesis of cholesterol. 30 Simvastatin(SIM) increased the proliferation of smaller MSCs, 30 and can increase osteogenesis of them. 31 The mechanism for enhancing osteogenesis is mediated by increasing both actin filament organization and cell rigidity.…”

The effects of simvastatin on cellular viability, stemness and osteogenic differentiation using 3-dimensional cultures of stem cells and osteoblast-like cells

“…8 Simvastatin induces increased pluripotency and protects against cellular senescence in MSCs. 6 It also improves the migration of bone marrow-derived MSCs via the PI3K/AKT pathway, 14 and enhances the neurogenesis of cultured neural stem cells and elevates Notch-1 protein expression. 7 Simvastatin exhibits increased dentin sialoprotein and calcium deposition, and it has been suggested that it can promote odontoblastic differentiation in dental pulp stem cells.…”

“…5 The effects of simvastatin on mesenchymal stem cells (MSCs) have been observed in previous studies. [6][7][8][9] Simvastatin has been reported to increase the therapeutic effects of nucleus pulposus stem cells by increasing the number of those cells. 8 It has also been shown to induce enhanced proliferation of cultured neural stem cells.…”

“…7 Conversely, simvastatin has been reported to negatively modulate bone marrow MSC proliferation in a dose-dependent manner and to regulate the expression of proliferation-related genes. 6 One report showed that simvastatin both directly interfered with the proliferation of stem cells and promoted cell death. 9 Moreover, the effects of simvastatin on the differentiation potential of stem cells have not been clearly determined.…”

Identification of Gli1‐interacting proteins during simvastatin‐stimulated osteogenic differentiation of bone marrow mesenchymal stem cells

“…Decreased numbers of bone marrow mesenchymal stem cells (BMSCs) and unbalanced differentiation of osteoblasts and adipocytes are vital mechanisms underlying osteoporosis . Recent studies showed that simvastatin could promote bone formation and osteogenic differentiation of BMSCs, although the mechanism by which this occurs remains unknown. Signaling pathways capable of modulating osteogenic differentiation of BMSCs are considered potential targets of simvastatin activity .…”