Progesterone and spinal cord injury: the challenge of remyelination

LABOMBARDA F

Workshop; Oligodendrocyte Biology and remyelination; 2019

Spinal cord lesions result in chronic demyelination as a consequence of secondary injury. Although oligodendrocyteprecursor cells proliferate the differentiation program fails. Successful differentiation implies progressivedecrease of transcriptional inhibitors followed by upregulation of activators. Progesterone emerges as an antiinflammatoryand 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 numberand decreased mRNA expression of transcriptional inhibitors (Id2, Id4, hes5). However, mRNA expression oftranscriptional 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 andthe density of Olig2- expressing oligodendrocyte precursor cells. The differentiation program is regulated byextracellular signals which modify transcriptional factors and epigenetic players. As TGFβ1 is a known oligodendrocytedifferentiation factor which is regulated by progesterone in reproductive tissues, we assessed whetherTGFβ1 could mediate progesterone remyelinating actions after the lesion.Notwithstanding that astrocyte, oligodendrocyte precursor and microglial cell density increased after spinalcord injury, the number of these cells which expressed TGFβ1 remained unchanged regarding sham operatedrats. However, progesterone treatment increased TGFβ1 mRNA expression and the number of astrocytes andmicroglial TGFβ1 expressing cells which would indirectly enhance oligodendrocyte differentiation. Therefore,TGFβ1 arises as a potential mediator of progesterone differentiating effects on oligodendrocyte linage.