title: Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice.
abstract: 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 within the brain converted somatic cells to neural progenitors and neuroblasts. Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-induced experimental demyelination. Mice were gavaged with VPA for one week, and then inducible Oct4 expressing lentiviral particles were injected into the lateral ventricle. After one-week induction of Oct4, LPC was injected into the optic chiasm. 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 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 3rd ventricle. LPC injection caused extensive demyelination and significantly delayed the latency 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.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Dehghan
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Hesaraki
authors.affiliation: Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: J
authors.initials: J
authors.lastname: Mirnajafi-Zadeh
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Y
authors.initials: Y
authors.lastname: Fathollahi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. Electronic address: mjavan@modares.ac.ir.
authors.forename: M
authors.initials: M
authors.lastname: Javan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000187:drug effects; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects; D009897:Optic Chiasm / Q000187:drug effects*; D012038:Regeneration / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014635:Valproic Acid
keywords: Oct4 transcription factor; multiple sclerosis; myelin repair; trans-differentiation; valproic acid; visual-evoked potential