engleski

Dynamic expression of ATF3 as a novel tool to study endogenous spinal stem cells and their role in neuronal repair

Recent therapeutic strategies for central nervous system lesions have mostly focused on stem cells, which might provide trophic and immunomodulatory factors to the injured neuronal tissue, and may, thus, enhance axonal growth and contrast neuroinflammation, with the possibility to replace dead neurons. If endogenous neuronal spinal stem/progenitor cells (SPCs) could be exploited for cell-based regenerative treatments of spinal cord injuries, the risk of immune rejection and the need of the heterologous transplanted cells would be avoided. We have identified Activating Transcription Factor 3 (ATF3) as a novel dynamic marker for ependymal SPCs (nestin, vimentin and SOX2 positive) around the central canal of the neonatal or adult mammalian (rat and opossum) spinal cord. While quiescent rat ependymal cells show cytoplasmic ATF3 expression, during 24h in vitro these cells mobilize and acquire intense nuclear ATF3 staining. Their migratory pattern follows a centrifugal pathway toward the dorsal and ventral funiculi, termed funicular migratory stream (FMS). The FMS process precedes the strong proliferation of ependymal cells occurring only after 24 h in vitro. Pharmacological inhibition of MAPK-p38 and JNK/c-Jun (upstream effectors of ATF3 activation) prevents the FMS mobilization of ATF3 nuclear-positive cells. Excitotoxicity or ischemia-like conditions does not further enhance migration of ependymal cells at 24 h, suggesting that, at this early stage of damage, the FMS phenomenon had peaked and that more extensive repair processes are delayed beyond this time point. Additionally, we have shown that the pharmacological inhibition of glutamate, GABAA or glycine receptors has no influence on spinal stem cell activation in vitro, suggesting that the in vitro activation of spinal SPCs is not neuronal network dependent. The opossums (Monodelphis Domestica) are marsupials born immature and with the unique capacity during the first postnatal week to fully recover after spinal cord injury. We have found that the ATF3 expression in ependymal cells of newborn opossums is nuclear in the early period of development when regeneration is possible, suggesting the active state of SPCs and their possible role in regeneration of spinal tissue after injury. ATF3 is, therefore, a useful tool to identify endogenous spinal SPCs and to study their activation, migration and role in the regenerative capacity of the spinal tissue.

ependymal stem/progenitor cells, Activating Transcription Factor 3, spinal cord injury, regeneration, funicular migratory stream, opossum, rat

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