Progesterone effects on oligodendrocyte differentiation in injured spinal cord.

Spinal cord lesions result in chronic demyelination as a consequence of secondary injury. Although oligodendrocyte precursor cells proliferate the differentiation program fails. Successful differentiation implies progressive decrease of transcriptional inhibitors followed by upregulation of activators. Progesterone emerges as an anti-inflammatory and pro-myelinating agent which improves locomotor outcome after spinal cord injury. In this study, we have demonstrated that spinal cord injury enhanced oligodendrocyte precursor cell number and decreased mRNA expression of transcriptional inhibitors (Id2, Id4, hes5). However, mRNA expression of transcriptional activators (Olig2, Nkx2.2, Sox10 and Mash1) was down-regulated 3 days post injury. Interestingly, a differentiation factor such as progesterone increased transcriptional activator mRNA levels and the density of Olig2- expressing oligodendrocyte precursor cells. The differentiation program is regulated by extracellular signals which modify transcriptional factors and epigenetic players. As TGFβ1 is a known oligodendrocyte differentiation factor which is regulated by progesterone in reproductive tissues, we assessed whether TGFβ1 could mediate progesterone remyelinating actions after the lesion. Notwithstanding that astrocyte, oligodendrocyte precursor and microglial cell density increased after spinal cord injury, the number of these cells which expressed TGFβ1 remained unchanged regarding sham operated rats. However, progesterone treatment increased TGFβ1 mRNA expression and the number of astrocytes and microglial TGFβ1 expressing cells which would indirectly enhance oligodendrocyte differentiation. Therefore, TGFβ1 arises as a potential mediator of progesterone differentiating effects on oligodendrocyte linage.