Abstract
Receptor for advanced glycation end products (RAGE) signaling is involved in a series of cell functions after spinal cord injury (SCI). Our study aimed to elucidate the effects of RAGE signaling on the neuronal recovery after SCI. In vivo, rats were subjected to SCI with or without anti-RAGE antibodies micro-injected into the lesion epicenter. We detected Nestin/RAGE, SOX-2/RAGE and Nestin/MAP-2 after SCI by Western blot or immunofluorescence (IF). We found that neural stem cells (NSCs) co-expressed with RAGE were significantly activated after SCI, while stem cell markers Nestin and SOX-2 were reduced by RAGE blockade. We found that RAGE inhibition reduced nestin-positive NSCs expressing MAP-2, a mature neuron marker. RAGE blockade does not improve neurobehavior Basso, Beattie and Bresnahan (BBB) scores; however, it damaged survival of ventral neurons via Nissl staining. Through in vitro study, we found that recombinant HMGB1 administration does not lead to increased cytokines of TNF-α and IL-1β, while anti-RAGE treatment reduced cytokines of TNF-α and IL-1β induced by LPS via ELISA. Meanwhile, HMGB1 increased MAP-2 expression, which was blocked after anti-RAGE treatment. Hence, HMGB1/RAGE does not exacerbate neuronal inflammation but plays a role in promoting NSCs differentiating into mature neurons in the pathological process of SCI.
Highlights
Spinal cord injury patients usually lose their self-care ability, bring suffering to families and burden society
We demonstrated the effect of receptors advanced glycation end products (RAGE) blockade on the neural stem cells after SCI; we found that RAGE blockade suppressed endogenous nestin-positive stem cell transformation into mature MAP-2-positive cells
Endogenous neural stem cells co-expressed with RAGE were activated after SCI; RAGE blockade reduced nestin overexpression induced by SCI
Summary
Spinal cord injury patients usually lose their self-care ability, bring suffering to families and burden society. The injured cellular components of neuronal cells induce immune cell infiltration and excessive release of pro-inflammatory cytokines through binding with their receptors advanced glycation end products (RAGE)[4]. There are neural stem cells in the spinal cord of adults[9] that promote neurogenesis in development, growing and aging processes[10,11,12]. Nestin-positive stem cells can transform into astrocytes or other glial cells and promote nestin-positive cells in SCI that predominantly show a rise in neurons[23,24,25]. NSCs facilitate neuronal cell proliferation, migration and neurogenesis after SCI, which may bring hope for regeneration of the injured spinal cord. HMGB1/RAGE may play a role in endogenous neural stem cell differentiation in the process of SCI
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