Pluripotent Stem Cells for Brain Repair: Protocols and Preclinical Applications in Cortical and Hippocampal Pathologies

et al. 2020

Preprint

Abstract Background Heat stroke (HS) is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Currently, mesenchymal stem cells (MSCs) have inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on HS-induced excessive inflammation and neurological dysfunction. Methods A heat stroke Sprague-Dawley (SD) rat model was established at continuous high temperature (42 °C) and high humidity (70%-80%). After modeling, the rats were randomly divided into a heat stroke model group (HS group), a MSCs treatment group (HS + MSCs group), and a Control group in which the rats were kept at room temperature without any treatment. Survival analysis, neurological deficit scoring, pathological staining of hippocampus and cerebellum, immunofluorescence staining of microglia cells, and tissue level detection of inflammatory cytokines were performed in the three groups on day 1, 3, 7, 14 and 28 separately. Results After heat stroke modeling, the rats were severely paralyzed and had a high mortality. MSCs treatment significantly reduced the mortality in both early stage (day 3) and late stage (day 28). MSCs treatment also significantly reduced the neurological impairment of heat stroke rats, and improved hippocampal and cerebellar pathology and neuronal cell damage. In addition, MSCs treatment significantly inhibited the overactivation of microglia in the hippocampus of HS rats as well as the levels of pro-inflammatory factors and chemokines in the hippocampus. In the early stage (day 1) of MSCs treatment, the activation of cerebellar microglia in the heat stroke rats was significantly promoted. Meanwhile, MSCs treatment had no significant inhibitory effect on the levels of pro-inflammatory factors in the cerebellar tissues of heat stroke rats, but can inhibit the levels of chemokines in the early stage. Conclusions The application of MSCs for heat stroke treatment in rats can significantly reduce the mortality and neurological defects and improve the hippocampal injury. Meanwhile, MSCs can inhibit the over-activation of microglia cells in the hippocampus of heat stroke rats, which may be a mechanism of MSCs in protecting heat-stroke-caused hippocampal injury.

Section: Discussionmentioning

confidence: 57%

Mesenchymal stem cells regulate activation of microglia cells to improve hippocampal nerve damage of heat stroke rats

Wang

Zhao

et al. 2020

Preprint

“…MSCs have signi cant protective effects on cerebral ischemic injuries, external injury caused by brain damage, Alzheimer's disease, dementia, Parkinson's disease and other neurodegenerative diseases. The speci c mechanisms include: MSCs can secrete various neurotrophic factors, regulate immune response, improve cerebral vascular permeability, and adjust nerve cell communication (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

“…At present, there is still no effective targeted method for treatment of heat stroke, especially for brain injury. Studies have con rmed that mesenchymal stem cells (MSCs) have a strong immune regulatory capacity, and can secret or induce the production of cytokines that have a signi cant protective effect on various brain injuries (12)(13)(14). However, the protective effect of MSCs on brain injury caused by radiation diseases has been seldom studied.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Regulate Activation of Microglia Cells to Improve Hippocampal Nerve Damage of Heat Stroke Rats

Wang

Zhao

et al. 2020

Preprint

Background: Heat stroke (HS) is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Currently, mesenchymal stem cells (MSCs) have inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on HS-induced excessive inflammation and neurological dysfunction.Methods: A heat stroke Sprague-Dawley (SD) rat model was established at continuous high temperature (42 °C) and high humidity (70%-80%). After modeling, the rats were randomly divided into a heat stroke model group (HS group), a MSCs treatment group (HS+MSCs group), and a Control group in which the rats were kept at room temperature without any treatment. Survival analysis, neurological deficit scoring, pathological staining of hippocampus and cerebellum, immunofluorescence staining of microglia cells, and tissue level detection of inflammatory cytokines were performed in the three groups on day 1, 3, 7, 14 and 28 separately.Results: After heat stroke modeling, the rats were severely paralyzed and had a high mortality. MSCs treatment significantly reduced the mortality in both early stage (day 3) and late stage (day 28). MSCs treatment also significantly reduced the neurological impairment of heat stroke rats, and improved hippocampal and cerebellar pathology and neuronal cell damage. In addition, MSCs treatment significantly inhibited the overactivation of microglia in the hippocampus of HS rats as well as the levels of pro-inflammatory factors and chemokines in the hippocampus. In the early stage (day 1) of MSCs treatment, the activation of cerebellar microglia in the heat stroke rats was significantly promoted. Meanwhile, MSCs treatment had no significant inhibitory effect on the levels of pro-inflammatory factors in the cerebellar tissues of heat stroke rats, but can inhibit the levels of chemokines in the early stage.Conclusions: The application of MSCs for heat stroke treatment in rats can significantly reduce the mortality and neurological defects and improve the hippocampal injury. Meanwhile, MSCs can inhibit the over-activation of microglia cells in the hippocampus of heat stroke rats, which may be a mechanism of MSCs in protecting heat-stroke-caused hippocampal injury.

“…Currently, mesenchymal stem cell (MSC)-based therapy is being considered as a potential treatment strategy for CNS injury (11)(12)(13). MSCs possess multipotent properties, such as the capacity to secrete various factors, differentiation potential, and immunoregulatory effects (14).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Provide Neuroprotection by Regulating Heat Stroke-Induced Brain Inflammation

Zhang

et al. 2020

Front. Neurol.

Heat stroke (HS) is the most acute type of heat illness accompanied with serious central nervous system (CNS) dysfunction. Despite the pathological process being clearly studied, effective treatment is deficient. Currently, mesenchymal stem cells (MSCs) have been demonstrated to have neuroprotective effects as there are no old ones. Thus, the purpose of the present study was to explore the neuroprotective effects and mechanisms of MSCs against HS-induced CNS injury. HS in rat models was induced by a high-temperature environment and treated with MSCs via the tail vein. The results demonstrated that MSC injection significantly reduced the mortality and inhibited the circulation inflammatory response. Moreover, the HS-induced neurological deficit and neuronic damage of the hippocampus were significantly ameliorated by MSC administration. In addition, MSC administration significantly restored astrocytes and inhibited cerebral inflammatory response. These results indicate that MSC infusion has therapeutic effects in HS of rats by regulating the circulation and cerebral inflammatory response. Moreover, astrocytes increased in MSC-treated HS rats when compared with the untreated ones. This may suggest a potential mechanism for HS prevention and therapy through MSC administration.