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Mesenchymal stem cells maintain the microenvironment of central nervous system by regulating the polarization of macrophages/microglia after traumatic brain injury

ABSTRACT Mesenchymal stem cells (MSCs), which are regarded as promising candidates for cell replacement therapies, are able to regulate immune responses after traumatic brain injury (TBI). Secondary immune response following the mechanical injury is the essential factor leading to the necrosis and apoptosis of neural cells during and after the cerebral edema has subsided and there is lack of efficient agent that can mitigate such neuroinflammation in the clinical application. By means of three molecular pathways (prostaglandin E2 (PGE2), tumor-necrosis-factor-inducible gene 6 protein (TSG-6), and progesterone receptor (PR) and glucocorticoid receptors (GR)), MSCs induce the activation of macrophages/microglia and drive them polarize into the M2 phenotypes, which inhibits the release of pro-inflammatory cytokines and promotes tissue repair and nerve regeneration. The regulation of MSCs and the polarization of macrophages/microglia are dynamically changing based on the inflammatory environment. Under the stimulation of platelet lysate (PL), MSCs also promote the release of pro-inflammatory cytokines. Meanwhile, the statue of macrophages/microglia exerts significant effects on the survival, proliferation, differentiation and activation of MSCs by changing the niche of cells. They form positive feedback loops in maintaining the homeostasis after TBI to relieving the secondary injury and promoting tissue repair. MSC therapies have obtained great achievements in several central nervous system disease clinical trials, which will accelerate the application of MSCs in TBI treatment.