RESEARCH ARTICLE The PTEN Inhibitor Bisperoxovanadium Enhances Myelination by Amplifying IGF-1 Signaling in Rat and Human Oligodendrocyte Progenitors Marcio L. De Paula, 1,2 Qiao-Ling Cui, 3 Shireen Hossain, 1 Jack Antel, 2,3 and Guillermina Almazan 1,2 Oligodendrocytes (OLGs) produce and maintain myelin in the central nervous system (CNS). In the demyelinating autoimmune disease multiple sclerosis, OLGs are damaged and those remaining fail to fully remyelinate CNS lesions. Therefore, current therapies directed to restrain the inflammation process with approaches that protect and reconstitute oligodendrocyte den- sity would be essential to pave the way of myelin repair. A critical signal for oligodendrocytes is insulin-like growth factor-1 (IGF-1), which promotes their development and ultimately myelin formation. PTEN inhibits the phosphoinositide 3-kinase (PI3K)=Akt signaling, a convergence downstream pathway for growth factors such as IGF-1. In this report, we temporarily inhibited PTEN activity by treating rat and human oligodendrocyte progenitors (OLPs) cultured alone or with dorsal root gan- glion neurons (DRGNs) with bisperoxovanadium (phen). Our findings show that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K=Akt=mammalian target of rapamycin (mTOR) and MEK=ERK. At low concentrations, IGF-1 and phen stimulated the differentiation of rat and human OLPs. Concordantly, the PTEN inhibitor together with IGF-1 robustly aug- mented myelin basic protein accumulation in rat newborn and human fetal OLGs co-cultured with DRGNs in a longer time- frame by promoting the elaboration of organized myelinated fibers as evidenced by confocal microscopy. Thus, our results suggest that a transient suppression of a potential barrier for myelination in combination with other therapeutic approaches including growth factors may be promising to improve the functional recovery of CNS injuries. GLIA 2014;62:64–77 Key words: myelin, multiple sclerosis, PI3K, differentiation, growth factors Introduction T he process of myelination in the central nervous system (CNS) involves generation of oligodendrocyte progenitors (OLPs), their migration to specific brain regions and finally, their differentiation into oligodendrocytes (OLGs), which synthesize myelin components to elaborate myelin sheaths (Small et al., 1987). Multiple signals are required for OLG development, including growth factors, neurotransmitters and hormones, which act in concert with developmental gene expression programs (Cohen and Almazan, 1994; McMorris and Dubois-Dalcq, 1988). The OLG-myelin-axon unit represents a unique struc- tural and functional specialization in the CNS. Myelin not only increases an axon’s diameter, which enhances conduction velocity, but also provides protection and trophic support (Wilkins et al., 2003). Disruption of these critical factors is present in the early stages of demyelinating diseases such as multiple sclerosis (MS) (Trapp et al., 1998). MS is primarily View this article online at wileyonlinelibrary.com. DOI: 10.1002/glia.22584 Published online October 26, 2013 in Wiley Online Library (wileyonlinelibrary.com). Received July 5, 2013, Accepted for publication Sep 18, 2013. Address correspondence to Guillermina Almazan, Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Room 1321, Montreal, Quebec, Canada H3G 1Y6. E-mail: guillermina.almazan@mcgill.ca From the 1 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; 2 Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; 3 Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Additional Supporting Information may be found in the online version of this article. 64 V C 2013 Wiley Periodicals, Inc.