Statin treatment of adult human glial progenitors induces PPARγ‐mediated oligodendrocytic differentiation

Abstract

The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARgamma, and could be blocked by the specific PPARgamma antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.

Statin Therapy Inhibits Remyelination in the Central Nervous System

“…The observed increase in Olig2 strong OPCs in the CC at this time is unlikely to reflect enhanced migration or proliferation given that simvastatin inhibits rodent OPC migration and human progenitor proliferation in vitro. 9,10 Our postulate is supported by the finding that OPC differentiation requires the acquisition of distinct sets of cholesterolenriched lipid rafts. 37 We also observed that the number of Nkx2.2 strong cells were significantly more reduced when simvastatin was administered to cuprizone-fed animals for weeks 4 to 9 in comparison with weeks 7 to 9, thereby indicating that prolonged exposure to the drug may be associated with more pronounced effects on these cells.…”

“…Exposure to simvastatin in vitro can hinder progenitor cell migration, inhibit proliferation, and exert a cytotoxic effect. 9,10 Previous studies in the experimental autoimmune encephalomyelitis model showed that lovastatin treatment (3 weeks) enhanced OPC proliferation, differentiation, and recruitment to the spinal cord. 8 Such statin therapy significantly inhibits the immune response within the experimental autoimmune encephalomyelitis-afflicted CNS, 6 raising the issue as to whether the net observed effects are indirectly mediated through anti-inflammatory effects.…”

“…9 Other studies have demonstrated that statin treatment of adult human brain-derived OPCs also enhances their differentiation while inhibiting proliferation. 10 Prolonged exposure to statins, however, can cause oligodendroglial process retraction through cholesterol depletion, and cell death by blocking synthesis of isoprenoids and cholesterol. 9 Given the multiple in vitro effects of statins on progenitor cell responses that are presumed to be implicated in remyelination, the objective of this study was to assess whether these observations translated into effects on remyelination in vivo.…”

Hyperforin promotes mitochondrial function and development of oligodendrocytes

“…PPAR-γ agonists are found to promote the differentiation of cultured spinal cord oligodendrocytes by the increasing percentage of cells expressing MBP (Roth et al, 2003). In another study, PPAR-γ agonists not only promote the differentiation of primary rat OPCs but also enhance their antioxidant defenses by increasing the levels of catalase and superoxide dismutase (Bernardo et al, 2009;Sim et al, 2008). A novel thiadiazolidinone, a PPAR-γ agonist, has shown antidepressant effects in the forced swimming test, and this effect is inhibited by PPAR-γ antagonists (Rosa et al, 2008).…”

Cell Therapy for Multiple Sclerosis

“…More recently, pharmacologic induction of OPC differentiation by inhibition of RhoA-Rho-kinase II (ROCK-II), and/or protein kinase C signaling [108], or by anti-Leucine-rich repeats and Ig domain-containing, neurite outgrowth inhibitor (Nogo) receptor-interacting protein-1 (LINGO1) antibodies [109,110] accelerated remyelination. Statins and inhibitors of receptor tyrosine phosphatases are other pharmacologic agents that induce rodent [111] and human [112] oligodendrocyte differentiation. However, when tested in the cuprizone model of demyelination in vivo, statin therapy inhibited remyelination [113].…”