Activation of PPAR‐γ and PTEN cascade participates in lovastatin‐mediated accelerated differentiation of oligodendrocyte progenitor cells

Abstract

Previously, we and others documented that statins including-lovastatin (LOV) promote the differentiation of oligodendrocyte progenitor cells (OPCs) and remyelination in experimental autoimmune encephalomyelitis (EAE), an multiple sclerosis (MS) model. Conversely, some recent studies demonstrated that statins negatively influence oligodendrocyte (OL) differentiation in vitro and remyelination in a cuprizone-CNS demyelinating model. Therefore, herein, we first investigated the cause of impaired differentiation of OLs by statins in vitro settings. Our observations indicated that the depletion of cholesterol was detrimental to LOV treated OPCs under cholesterol/serum-deprived culture conditions similar to that were used in conflicting studies. However, the depletion of geranylgeranyl-pp under normal cholesterol homeostasis conditions enhanced the phenotypic commitment and differentiation of LOV-treated OPCs ascribed to inhibition of RhoA-Rho kinase. Interestingly, this effect of LOV was associated with increased activation and expression of both PPAR-γ and PTEN in OPCs as confirmed by various pharmacological and molecular based approaches. Furthermore, PTEN was involved in an inhibition of OPCs proliferation via PI3K-Akt inhibition and induction of cell cycle arrest at G1 phase, but without affecting their cell survival. These effects of LOV on OPCs in vitro were absent in the CNS of normal rats chronically treated with LOV concentrations used in EAE indicating that PPAR-γ induction in normal brain may be tightly regulated -providing evidences that statins are therapeutically safe for humans. Collectively, these data provide initial evidence that statin-mediated activation of the PPAR-γ -PTEN cascade participates in OL differentiation, thus suggesting new therapeutic-interventions for MS or related CNS-demyelinating diseases.

Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

“…LRP1 conditional deletion in mature neurons under the control of the CAMKII promoter led to a significant reduction of cholesterol concentration in the CNS tissue (Liu et al 2010). Because oligodendroglial and neuronal differentiation presumably depend on the cholesterol concentration (Bieberich 2012; Orth and Bellosta 2012; Paintlia et al 2010), we proposed that the deprivation of cholesterol might result in the impaired differentiation. In order to test whether the cholesterol concentration has an effect on NSPCs differentiation, we chemically depleted cholesterol from the wild type, not Cre-treated NSPCs using methyl-β-cyclodextrin (MβCD).…”

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

“…Error bars represent mean 6 SD. Abbreviation: GGTI, geranylgeranyl transferase I. neuroblastoma cells [35,36]. This cell differentiation is mediated through the activation of the peroxisome proliferator-activated receptor gamma (PPAR)c-phosphatase and tensin homolog (PTEN) cascade and subsequent inhibition of phosphoinositide-3-kinase (PI3K)-AKT signaling.…”

S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological Conditions

“…OL Differentiation Studies-OLs/OL progenitor cells dislodged from the astrocyte layer were replated on laminin-2 coated glass chamber slides in high glucose Sato-based medium after checking their purity as described earlier (35). Purified OLs/OL progenitor cells (2000 cells/cm 2 ) were plated in glass chamber slides in Sato medium supplemented with PDGF-AA and bovine FGF-2 (10 ng/ml each).…”