Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

2-Chlorodeoxyadenosine (Cladribine) preferentially inhibits the biological activity of microglial cells.

Cladribine (2CdA) is a synthetic chlorinated purine nucleoside analogue which acts as a pro-drug requiring intracellular phosphorylation to be activated. It is biologically active in selected cell types, which results in a reduction of circulating T and B lymphocytes implicated in multiple sclerosis (MS) pathogenesis. In addition, 2CdA shows good central nervous system (CNS) penetration and can therefore exert its action on microglia and astrocytes. Therefore, we studied the effects of 2CdA on microglial cells and astrocytes, both emerging as potential targets for MS therapy. Other than its effects on the peripheral immune system, 2CdA induced the apoptosis of microglial cells, inhibited their proliferation and reduced the production of cytokines, particularly pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α. These represent additional mechanisms of 2CdA that may contribute to limiting inflammatory pathways. By contrast, astrocytes showed resistance to the action of 2CdA, which may be explained by differences in its intracellular phosphorylation. Insights into the mechanism of action of and resistance to 2CdA in CNS-resident cells may prove crucial for its optimal use.