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.

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

“…We also showed that MSCs effectively reduced the release of proinflammatory cytokines IL‐1α, IL‐1β, IL‐6, and TNF‐α, which are associated with the M1 phenotype. This is consistent with previous studies that various sources of MSCs are involved in microglial activation (Liu et al, ; Neubrand et al, ; Xu, Fu, Li, & Zhang, ). Although more detailed mechanisms need to be investigated, it is likely that MSCs interfere with thrombin‐mediated M1 polarization.…”

Intravenously Infusing the Secretome of Adipose-Derived Mesenchymal Stem Cells Ameliorates Neuroinflammation and Neurological Functioning After Traumatic Brain Injury

“…The transcriptome analysis of macrophage showed M1 and M2 phenotypes were the typical conditions and activated macrophages were showing a complicated plasticity that responds to particular pathological process [36]. Previous studies have shown that MSCs mediate the inflammatory response by regulating the polarization of microglia/ macrophages, preventing secondary insults [3,37], and PGE2, TSG-6, and TGF-b are considered major effective factors in the balance of M1/M2 phenotypes [38]. In this study, we regarded the ratio of M1/M2 as the reflection of the state of neuroinflammation after TBI [39].…”

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

“…TBI is characterized by external mechanical forces causing brain injury, which potentially cause physical, cognitive, and emotional impairments to the patients [131,132]. Due to the immunomodulatory properties of MSCs, their secretome may also be used to modulate the secondary injury mechanisms of TBI, controlling the exaggerated inflammatory response, reducing pro-inflammatory cytokines, and promoting an increase in neural stem cell proliferation and differentiation [133][134][135]. Several factors secreted by MSCs such as NGF, GDNF, BDNF, and Wnt3a could attenuate the loss of cholinergic neurons in the medial septum of mice and still promote hippocampal neurogenesis [136,137].…”