Transplantation of mesenchymal stem cells genetically engineered to overexpress interleukin-10 promotes alternative inflammatory response in rat model of traumatic brain injury

Abstract

BackgroundTraumatic brain injury (TBI) is a major cause for long-term disability, yet the treatments available that improve outcomes after TBI limited. Neuroinflammatory responses are key contributors to determining patient outcomes after TBI. Transplantation of mesenchymal stem cells (MSCs), which release trophic and pro-repair cytokines, represents an effective strategy to reduce inflammation after TBI. One such pro-repair cytokine is interleukin-10 (IL-10), which reduces pro-inflammatory markers and trigger alternative inflammatory markers, such as CD163. In this study, we tested the therapeutic effects of MSCs that were engineered to overexpress IL-10 when transplanted into rats following TBI in the medial frontal cortex.MethodsThirty-six hours following TBI, rats were transplanted with MSCs and then assessed for 3 weeks on a battery of behavioral tests that measured motor and cognitive abilities. Histological evaluation was then done to measure the activation of the inflammatory response. Additionally, immunomodulatory effects were evaluated by immunohistochemistry and Western blot analyses.ResultsA significant improvement in fine motor function was observed in rats that received transplants of MSCs engineered to overexpress IL-10 (MSCs + IL-10) or MSCs alone compared to TBI + vehicle-treated rats. Although tissue spared was unchanged, anti-inflammatory effects were revealed by a reduction in the number of glial fibrillary acidic protein cells and CD86 cells in both TBI + MSCs + IL-10 and TBI + MSC groups compared to TBI + vehicle rats. Microglial activation was significantly increased in the TBI + MSC group when compared to the sham + vehicle group. Western blot data suggested a reduction in tumor necrosis factor-alpha in the TBI + MSCs + IL-10 group compared to TBI + MSC group. Immunomodulatory effects were demonstrated by a shift from classical inflammation expression (CD86) to an alternative inflammation state (CD163) in both treatments with MSCs and MSCs + IL-10. Furthermore, co-labeling of both CD86 and CD163 was detected in the same cells, suggesting a temporal change in macrophage expression.ConclusionsOverall, our findings suggest that transplantation of MSCs that were engineered to overexpress IL-10 can improve functional outcomes by providing a beneficial perilesion environment. This improvement may be explained by the shifting of macrophage expression to a more pro-repair state, thereby providing a possible new therapy for treating TBI.

Transplantation of mesenchymal stem cells overexpressing interleukin‐10 induces autophagy response and promotes neuroprotection in a rat model of TBI

“…The MSCs were isolated and cultured as described previously . Viral production and their expression were confirmed from puromycin (10 µg/mL)‐selected colonies.…”

“…Several research reports suggested that MSC transplantation plays beneficial roles in the treatment of TBI, by releasing anti‐inflammatory chemokines, which can reduce neuronal injury . To augment the MSCs release of anti‐inflammatory cytokines, the use of genetically engineered MSCs that overexpress IL‐10 (MSCs‐IL‐10), delivered to injured brain areas . Recently, we found that the transplantation of MSCs‐IL‐10 promotes conversion of M1 to M2 macrophages, thereby increasing anti‐inflammatory cytokines and decreasing inflammatory responses in rats given TBI .…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…This pathway has been implicated in epilepsy; using hippocampal cultures from a picrotoxin‐mediated seizure model in mice, IL‐10 overexpression was able to suppress IL‐1β expression . Using the closed cortical impact model of TBI, M2 polarization was induced by IL‐10 secretion from transplanted, genetically modified MSCs . The M2 polarized microglia in the CA1 area of the hippocampus led to improvements in fine motor skills and prevented cell loss .…”

“…75 Using the closed cortical impact model of TBI, M2 polarization was induced by IL-10 secretion from transplanted, genetically modified MSCs. 76 The M2 polarized microglia in the CA1 area of the hippocampus led to improvements in fine motor skills and prevented cell loss. 76 Similar beneficial effects of IL-10 administration have been reported after fluid-percussion TBI.…”

“…76 The M2 polarized microglia in the CA1 area of the hippocampus led to improvements in fine motor skills and prevented cell loss. 76 Similar beneficial effects of IL-10 administration have been reported after fluid-percussion TBI. 77 IL-10 expressing MSCs can also induce M2 polarization in other brain pathologies that have epileptogenic potential such as stroke and improve functional outcomes.…”