Differential and Cooperative Actions of Olig1 and Olig2 Transcription Factors on Immature Proliferating Cells After Contusive Spinal Cord Injury

Abstract

Spontaneous remyelination after spinal cord injury (SCI) is limited probably due to inadequate signaling to generate sufficient OLs from progenitor cells. The present study tested a hypothesis that introduction of olig genes, critical regulators of OL development, into immature proliferating cells could increase oligodendrogenesis after contusive SCI in adult rats. Recombinant retroviruses encoding Olig1 and Olig2 transcription factors, separately or in combination, with green fluorescent protein (GFP) were injected into the injured spinal cord. Unexpectedly, introduction of Olig2-GFP retroviruses led to a marked hyperplasia of GFP+ cells at 1 week, and soft agar colony forming assay of isolated GFP+ cells confirmed Olig2-induced tumorous transformation. In contrast, Olig1 did not alter the number of GFP+ cells. Simultaneous expression of Olig1 and Olig2 (Olig1/2) led to a marked increase in the number of GFP+ cells without tumor formation. The proportion of GFP+ cells with OL progenitor markers was increased by Olig1/2. Moreover, Olig1/2 robustly increased the proportion of mature OLs and expression of myelin related proteins, while Olig1 alone exhibited only modest effects. Olig1/2 up-regulated Sox10, which drives terminal OL differentiation, implicating Sox 10 as a mediator of Olig1/2 effects on the maturation. Finally, injection of Olig1/2 retroviruses significantly improved a quality of hindpaws locomotion and increased the total number of OLs after SCI. Activation of both Olig1 and Olig2 may be beneficial by both increasing the progenitor cell proliferation and enhancing OL differentiation in the injured spinal cord.