Conditioned medium from mesenchymal stem cells reduces microglia inflammatory response by regulating MAPK and STAT1 pathways

Abstract

Hemorrhage in the brain frequently occurs for various reasons such as trauma or ischemia and leads to significant mortality and life-long neurological complications. Reactive gliosis is a reaction that microglia and astrocytes are abnormally proliferate and hypertrophic in response to assorted insults, infections, and diseases. In particular, microglia, the resident immune cells in the brain, could be a potential target to prevent or reduce neurological disorders. Despite acute and severe immune responses after severe intraventricular hemorrhage, our understanding of signaling pathways which trigger microglial activation after the bleeding is relatively less clear. Nevertheless, mesenchymal stem cells conditioned medium (MSC-CM) could be an attractive source of therapies for this neurological disorder. In this study, I investigated signaling pathways for microglial activation in response to thrombin, a major component of the blood which readily become active in hemorrhagic conditions. When cultured microglial cells were exposed to thrombin in vitro, they increase in number and somal size and displayed ameboid shape as a sign of gliosis. I observed that thrombin triggered activation of STAT1, p38 MAPK, and p44/42 ERK. Interestingly, this activation was reduced by MSC-CM which contains a variety of unknown factors. This coincided with increase of transcript level of major pro-inflammatory cytokine. Lastly, thrombin-induced cytokine transcript level became low when MSC-CM was applied. Together, these results revealed that MSC-CM has a potential to rescue the severe intraventricular hemorrhage by regulating of JAK-STAT and MAPK signaling pathways.