Statin treatment of adult human glial progenitors induces PPAR gamma-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.