Multiple sclerosis is a demyelinating disease with severe neurological symptoms due to blockage of signal conduction in affected axons. Spontaneous remyelination via endogenous progenitors is limited and eventually fails. Recent reports showed that forced expression of some transcription factors (factors that control making proteins) within the brain converted cells to neural progenitors and neuroblasts (cells that make nerves). Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-(toxin that kills oligodendrocytes) induced experimental demyelination. Mice were gavaged (fed) with VPA for one week, and then inducible Oct4 expressing lentiviral particles (gene therapy vector) were injected into the lateral ventricle (fluid filled space in the brain). After one-week induction of Oct4, LPC was injected into the optic chiasm (bit where optic nerves leave the brain) . Functional remyelination was assessed by visual-evoked potential (VEP) recording. Myelination level was studied using FluoroMyelin staining and immunohistofluorescent (IHF) against proteolipid protein (PLP). IHF was also performed to detect Oct4 and SSEA1 as pluripotency markers (stem cell markers) and Olig2, Sox10, CNPase and PDGFRα as oligodendrocyte lineage markers. One week after injection of Oct4 expressing vector, pluripotency markers SSEA1 and Oct4 were detected in the rims of the ventricle. LPC injection caused extensive demyelination and significantly delayed the latency (delay) of VEP wave. Animals pre-treated with VPA+Oct4 expressing vector, showed faster recovery in the VEP latency and enhanced myelination. Immunostaining against oligodendrocyte lineage markers showed an increased number of Sox10+ and myelinating cells. Moreover, transdifferentiation of some Oct4-transfected cells (GFP+ cells) to Olig2+ and CNPase+ cells was confirmed by immunostaining. One-week administration of VPA followed by one-week forced expression of Oct4 enhanced myelination by converting transduced cells to myelinating oligodendrocytes. This finding seems promising for enhancing myelin repair within the adult brains.
Dehghan S, Hesaraki M, Soleimani M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M. Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice. Neuroscience. 2016 . pii: S0306-4522(16)00047-6.
So more ways to make myelin