A proteomic investigation into mechanisms underpinning corticosteroid effects on neural stem cells

Abstract

Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label-free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects.

New insights into the effects of caffeine on adult hippocampal neurogenesis in stressed mice: Inhibition of CORT‐induced microglia activation

“…The results showed that BV‐2 cells activated by CORT significantly inhibited the proliferation and differentiation of NSCs. It is worthy to note that, CORT itself exerted inhibitory effect on the proliferation and differentiation of NSCs 73‐75 . It can be inferred from the above analysis that CORT‐induced microglia activation is an adverse factor for stress‐inhibited neurogenesis.…”

Untitled

“…Hematopoietic stem cells have self-renewal and multi-lineage differentiation properties, but larger studies need to be conducted in order to confirm these results [25]. Neural stem cells generate the major cell types found within the CNS (astrocytes, oligodendrocytes, and neurons), playing a key role in brain development [60]. However, collecting these cells from the brain or spinal cord is not easily accessible.…”

The Effects Of Stem Cells On Epilepsy

“…NSCs can synthesize glia secreting substances, which have anticonvulsant qualities, as well as GABA neurotransmitters [38]. NSCs are multipotent and believed to be capable of generating the major cell types of the CNS (astrocytes, neurons, and oligodendrocytes) [39]. In the adult brain neurogenesis is only located within two regions -the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampus [40].…”