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Published on: August 21, 2017
Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in
S Dehghan1, M Hesaraki2, M Soleimani3
1Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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.
Insights
Valproic acid and Oct4 expression promote myelin repair in demyelinated brains by converting cells into myelinating oligodendrocytes, offering a promising therapeutic strategy for multiple sclerosis.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Cell Biology
Background:
- Multiple sclerosis involves demyelination and neurological deficits.
- Spontaneous remyelination is limited and often fails.
- Transcription factors can reprogram somatic cells into neural progenitors.
Purpose of the Study:
- To investigate the effect of valproic acid (VPA) and Oct4 transcription factor on experimental demyelination.
- To assess the potential of VPA and Oct4 to enhance myelin repair in the adult brain.
Main Methods:
- Mice received VPA, followed by lentiviral Oct4 expression induction.
- Lysolecithin-induced demyelination was induced in the optic chiasm.
- Functional recovery (VEP), myelination (FluoroMyelin, PLP), and cell lineage (Oct4, SSEA1, Olig2, Sox10) were assessed.
Main Results:
- VPA + Oct4 treatment accelerated VEP recovery and enhanced myelination.
- Increased numbers of Sox10+ and myelinating cells were observed.
- Transdifferentiation of Oct4-transfected cells into myelinating oligodendrocytes was confirmed.
Conclusions:
- VPA and Oct4 administration promote myelin repair by inducing cell transdifferentiation into oligodendrocytes.
- This approach shows promise for enhancing myelin repair in adult brains affected by demyelinating diseases.
