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Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury.

ABSTRACT: Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia (33°C) was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the mRNA expression of the proinflammatory cytokines interleukin-1?, tumor necrosis factor-? and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.

SUBMITTER: Zhao K

PROVIDER: S-EPMC6128055 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury.

Zhao Kai K Li Rui R Bi Sheng S Li Yu Y Liu Long L Jia Yu-Long YL Han Peng P Gu Chang-Cong CC Guo Xi-Ze XZ Zhang Wan-Ping WP Wang Chun C Pei Chun-Ying CY Tian Lin-Lu LL Li Li-Xian LX

Neural regeneration research 20181001 10

Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery ...[more]

PMID: 30136691

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Project description:BackgroundAnal sphincter injury leads to fecal incontinence. Based on the regenerative capability of laser and human adipose-derived stem cells (hADSCs), this study was designed to assess the effects of co-application of these therapies on anal sphincter recovery after injury.DesignMale rabbits were assigned to equal groups (n?=?7) including control, sphincterotomy, sphincterotomy treated with laser (660?nm, 90 s, immediately after sphincterotomy, daily, 14?days), hADSCs (2?×?106 hADSCs injected into injured area of the sphincter immediately after sphincterotomy), and laser?+?hADSCs. Ninety?days after sphincterotomy, manometry and electromyography were performed, sphincter collagen content was evaluated, and Ki67, myosin heavy chain (MHC), skeletal muscle alpha-actin (ACTA1), vascular endothelial growth factor A (VEGFA), and vimentin mRNA gene expression were assessed.ResultsThe laser?+?hADSCs group had a higher resting pressure compared with the sphincterotomy (p?<?0.0001), laser (p?<?0.0001), and hADSCs (p?=?0.04) groups. Maximum squeeze pressure was improved in all treated animals compared with the sphincterotomized animals (p?<?0.0001), without a significant difference between treatments (p?>?0.05). In the laser?+?hADSCs group, motor unit numbers were higher than those in the laser group (p?<?0.0001) but did not differ from the hADSCs group (p?=?0.075). Sphincterotomy increased collagen content, but the muscle content (p?=?0.36) and collagen content (p?=?0.37) were not significantly different between the laser?+?hADSCs and control groups. Laser?+?hADSCs increased ACTA1 (p?=?0.001) and MHC (p?<?0.0001) gene expression compared with laser or hADSCs alone and was associated with increased VEGFA (p?=?0.009) and Ki67 mRNA expression (p?=?0.01) and decreased vimentin mRNA expression (p?<?0.0001) compared with laser.ConclusionThe combination of laser and hADSCs appears more effective than either treatment alone for promoting myogenesis, angiogenesis, and functional recovery after anal sphincterotomy.

Project description:BackgroundNeonatal encephalopathy due to hypoxia-ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice.MethodsNine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry.ResultsImmediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT.ConclusionOur data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.

Project description:ImportanceTherapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of therapeutic hypothermia to date have not included infants with mild HIE because of a perceived good prognosis.ObjectiveTo test the hypothesis that children with mild HIE have worse neurodevelopmental outcomes than their healthy peers.Design, setting, and participantsAnalysis of pooled data from 4 prospective cohort studies in Cork, Ireland, and Stockholm, Sweden, between January 2007 and August 2015. The dates of data analysis were September 2017 to June 2019. Follow-up was performed at age 18 to 42 months. In this multicenter cohort study, all children were born or treated at the tertiary centers of Cork University Maternity Hospital, Cork, Ireland, or Karolinska University Hospital, Stockholm, Sweden. In all, 690 children were eligible for this study.ExposuresAt discharge, all children were categorized into the following 5 groups using a modified Sarnat score: healthy controls, perinatal asphyxia (PA) without HIE, mild HIE, moderate HIE, and severe HIE.Main outcomes and measuresCognitive, language, and motor development were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III). The BSITD-III scores are standardized to a mean (SD) of 100 (15), with lower scores indicating risk of developmental delay.ResultsOf the 690 children eligible for this study, 2-year follow-up data were available in 471 (mean [SD] age at follow-up, 25.6 [5.7] months; 54.8% male), including 152 controls, 185 children with PA without HIE, and 134 children with HIE, of whom 14 had died. Infants with mild HIE (n = 55) had lower cognitive composite scores compared with controls, with a mean (SD) of 97.6 (11.9) vs 103.6 (14.6); the crude mean difference was -6.0 (95% CI, -9.9 to -2.1), and the adjusted mean difference was -5.2 (95% CI, -9.1 to -1.3). There was no significant difference in the mean cognitive composite scores between untreated children (n = 47) with mild HIE and surviving children with moderate HIE (n = 53) treated with therapeutic hypothermia, with a crude mean difference for mild vs moderate of -2.2 (95% CI, -8.1 to 3.7).Conclusions and relevanceThis study's findings suggest that, at age 2 years, the cognitive composite scores of children with a history of mild HIE may be lower than those of a contemporaneous control group and may not be significantly different from those of survivors of moderate HIE treated with therapeutic hypothermia.

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Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury.

Publications

Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury.

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