Abstract
Mesenchymal stem cell (MSC) transplantation reduces the neurological impairment caused by hypoxic-ischemic brain damage (HIBD) via immunomodulation. In the current study, we found that MSC transplantation improved learning and memory function and enhanced long-term potentiation in neonatal rats subjected to HIBD and the amount of IL-6 released from MSCs was far greater than that of other cytokines. However, the neuroprotective effect of MSCs infected with siIL-6-transduced recombinant lentivirus (siIL-6 MSCs) was significantly weakened in the behavioural tests and electrophysiological analysis. Meanwhile, the hippocampal IL-6 levels were decreased following siIL-6 MSC transplantation. In vitro, the levels of IL-6 release and the levels of IL-6R and STAT3 expression were increased in both primary neurons and astrocytes subjected to oxygen and glucose deprivation (OGD) following MSCs co-culture. The anti-apoptotic protein Bcl-2 was upregulated and the pro-apoptotic protein Bax was downregulated in OGD-injured astrocytes co-cultured with MSCs. However, the siIL-6 MSCs suppressed ratio of Bcl-2/Bax in the injured astrocytes and induced apoptosis number of the injured astrocytes. Taken together, these data suggest that the neuroprotective effect of MSC transplantation in neonatal HIBD rats is partly mediated by IL-6 to enhance anti-apoptosis of injured astrocytes via the IL-6/STAT3 signaling pathway.
Highlights
Via the Janus-associated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, the Ras– Raf–mitogen-activated protein kinase (MAPK) pathway and the PI3K/Akt pathway[12,13]
The field excitatory postsynaptic potentials in the hippocampal CA1 region of brain slices from each group were recorded to examine the effects of MSC transplantation on hippocampal synaptic plasticity
The slope of the field excitatory postsynaptic potentials (fEPSPs) in the hypoxic-ischemic brain damage (HIBD) + MSCs group (134.2% ± 4.3%; Fig. 1G) was more than that in the HIBD group despite that the difference was with no significant. These results demonstrated that MSC transplantation alleviated the memory impairment of rats subjected to HIBD
Summary
Via the Janus-associated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, the Ras– Raf–mitogen-activated protein kinase (MAPK) pathway and the PI3K/Akt pathway[12,13]. In the central nervous system (CNS), the IL-6 levels are low under normal conditions but are significantly elevated under disease conditions. Both detrimental and beneficial functions of this cytokine have been reported[14,15], but the exact role of this cytokine following MSC transplantation has not been established. We treated neonatal HIBD rats with MSCs infected with siIL-6-transduced lentivirus (siIL-6 MSCs) to verify the biological role of IL-6 in promoting the recovery of learning and memory deficits in rats subjected to HIBD. The results of this study may provide supporting information for the clinical application of MSCs
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