Abstract
BackgroundContusive spinal cord injury is complicated by a delayed loss of oligodendrocytes, resulting in chronic progressive demyelination. Therefore, transplantation strategies to provide oligodendrocyte lineage cells and to enhance the extent of myelination appear to be justified for spinal cord repair. The present study investigated whether transplantation of human neural stem cells (NSCs) genetically modified to express Olig2 transcription factor, an essential regulator of oligodendrocyte development, can improve locomotor recovery and enhance myelination in a rat contusive spinal cord injury model.ResultsHB1.F3 (F3) immortalized human NSC line was transduced with a retroviral vector encoding Olig2, an essential regulator of oligodendrocyte development. Overexpression of Olig2 in human NSCs (F3.Olig2) induced activation of NKX2.2 and directed differentiation of NSCs into oligodendrocyte lineage cells in vitro. Introduction of Olig2 conferred higher proliferative activity, and a much larger number of F3.Olig2 NSCs were detected by 7 weeks after transplantation into contused spinal cord than that of parental F3 NSCs. F3.Olig2 NSCs exhibited frequent migration towards the white matter, whereas F3 NSCs were mostly confined to the gray matter or around the lesion cavities. Most of F3.Olig2 NSCs occupying the spared white matter differentiated into mature oligodendrocytes. Transplantation of F3.Olig2 NSCs increased the volume of spared white matter and reduced the cavity volume. Moreover, F3.Olig2 grafts significantly increased the thickness of myelin sheath around the axons in the spared white matter. Finally, animals with F3.Olig2 grafts showed an improvement in the quality of hindlimbs locomotion.ConclusionTransplantation of NSCs genetically modified to differentiate into an oligodendrocytic lineage may be an effective strategy to improve functional outcomes following spinal cord trauma. The present study suggests that molecular factors governing cell fate decisions can be manipulated to enhance reparative potential of the cell-based therapy.
Highlights
Contusive spinal cord injury is complicated by a delayed loss of oligodendrocytes, resulting in chronic progressive demyelination
F3.Olig2 neural stem cells (NSCs) in the spared white matter express myelin basic protein (MBP) (Figure 4I-J), a cell type specific marker for myelinating oligodendrocytes, suggesting that F3.Olig2 cells in the spared white matter differentiated into mature oligodendrocytes that were capable of producing myelin
This finding is consistent with the recent reports that overexpression of Olig2 transcription factor is sufficient to induce the expression of Nkx2.2 and differentiation of neural stem/progenitor cells into oligodendrocytes [35,36]
Summary
Contusive spinal cord injury is complicated by a delayed loss of oligodendrocytes, resulting in chronic progressive demyelination. Absence of myelin sheath and resultant exposure of potassium channels lead to a failure of electrical conduction through spared axons, contributing to chronic functional deficits following SCI [10] From these observations, transplantation strategies to provide cells capable of myelinating axons and enhance remyelination seem to be well justified for spinal cord repair. A large part of behavioral gains following grafts of murine neural stem cells without lineage restriction has recently been attributed to an enhanced myelination in the spared white matter [14,15] These studies indicate that enhancing myelination by transplantation of stem/progenitor cells is a promising approach to improve functional outcomes for patients suffering from SCI
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