scholarly journals Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

2019 ◽  
Vol 21 (1) ◽  
pp. 181 ◽  
Author(s):  
Maheedhar Kodali ◽  
Olagide W. Castro ◽  
Dong-Ki Kim ◽  
Alicia Thomas ◽  
Bing Shuai ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Brain Injury ◽  
Extracellular Vesicles ◽  
Brain Regions ◽  
Great Promise ◽  
Hippocampal Ca1 ◽  
Marrow Mesenchymal Stem Cells ◽  
Multiple Regions ◽  
Rat Forebrain ◽  
Serial Brain

Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the procedure is noninvasive, amenable for repetitive dispensation, and leads to a quick penetration of EVs into multiple regions of the forebrain. Nonetheless, it is unknown whether brain injury-induced signals are essential for the entry of IN-administered EVs into different brain regions. Therefore, in this study, we investigated the distribution of IN-administered hMSC-derived EVs into neurons and microglia in the intact and status epilepticus (SE) injured rat forebrain. Ten billion EVs labeled with PKH26 were dispensed unilaterally into the left nostril of naïve rats, and rats that experienced two hours of kainate-induced SE. Six hours later, PKH26 + EVs were quantified from multiple forebrain regions using serial brain sections processed for different neural cell markers and confocal microscopy. Remarkably, EVs were seen bilaterally in virtually all regions of intact and SE-injured forebrain. The percentage of neurons incorporating EVs were comparable for most forebrain regions. However, in animals that underwent SE, a higher percentage of neurons incorporated EVs in the hippocampal CA1 subfield and the entorhinal cortex, the regions that typically display neurodegeneration after SE. In contrast, the incorporation of EVs by microglia was highly comparable in every region of the forebrain measured. Thus, unilateral IN administration of EVs is efficient for delivering EVs bilaterally into neurons and microglia in multiple regions in the intact or injured forebrain. Furthermore, incorporation of EVs by neurons is higher in areas of brain injury, implying that injury-related signals likely play a role in targeting of EVs into neurons, which may be beneficial for EV therapy in various neurodegenerative conditions including traumatic brain injury, stroke, multiple sclerosis, and Alzheimer’s disease.

scholarly journals Early Transfusion with Mesenchymal Stem Cell Derived Extracellular Vesicles: A New Transfusion Strategy for Life-Threatening Hemorrhage and Traumatic Brain Injury

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1071-1071
Author(s):  
Simone E Dekker ◽  
Ted Bambakidis ◽  
Aaron M Williams ◽  
Ben Biesterveld ◽  
Umar Bhatti ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Extracellular Vesicles ◽  
Porcine Model ◽  
Conflicts Of Interest ◽  
Great Promise ◽  
Bioinformatics Analyses ◽  
Area Of Interest ◽  
Life Threatening ◽  
Severe Tbi

Abstract Background: Life-threatening hemorrhage and traumatic brain injury (TBI) have a significantly increasing global burden and remain leading causes of preventable deaths. Effective interventions may protect the brain against ongoing damage and improve the long-term outcomes. A growing area of interest is transfusion of cell-based therapies, particularly with bone marrow-derived mesenchymal stem cells (MSC). Transfusion using MSC derived extracellular vesicles (EVs) have shown to improve neurologic outcomes in animal models of life-threatening hemorrhage, stroke, and TBI. However, the precise mechanisms remain poorly characterized. In the present study, we aimed to elucidate some of the key cerebral genes, pathways, and networks that were modulated after transfusion of EVs in a porcine model of hemorrhagic shock (HS) and TBI. Methods: Swine were subjected to HS (40% blood volume) and severe TBI (8-mm cortical impact). After 1 hour of shock, animals were randomized (n=4/group) to treatment with either lactated Ringer's (LR) or LR+EV. Both groups received fluid resuscitation after 2 hours of shock, and autologous packed red blood cells 5 hours later. After 7-days, brains were harvested and RNA-sequencing was performed. The transcriptomic data was imported into the iPathway pipeline for bioinformatics analyses. Results: 5,273 genes were differentially expressed in the LR+EV group vs. LR alone (total 9,588 measured genes, Figure 1). Table 1 lists the top 10 genes exhibiting the greatest up- and down-expression based on fold change. Genes with the greatest up-regulation were involved in synaptic transmission and neuronal development and differentiation, while down-regulated genes were involved in inflammation. Gene Ontology terms experiencing the greatest modulation were involved in inflammation, brain development, and cell adhesion. Pathway analysis revealed significant modulation in the glutamatergic and GABAergic systems. Network analysis revealed down-regulation of inflammation (Figure 2), and up-regulation of neurogenesis, and neuron survival and differentiation. Conclusions: In a porcine model of HS+TBI, EV transfusion was associated with an attenuation of cerebral inflammatory networks and a promotion of neurogenesis and neuroplasticity. These transcriptomic changes could explain the observed neuroprotective and neurorestorative properties associated with EV transfusion. EV transfusion reduces the hyper-inflammatory response and may have great promise in improving outcomes in concurrent life-threatening hemorrhage and severe TBI. Further testing of this novel strategy and its implications in transfusion medicine are warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kimberly F. Young ◽  
Rebeca Gardner ◽  
Victoria Sariana ◽  
Susan A. Whitman ◽  
Mitchell J. Bartlett ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Western Blot ◽  
Calcium Binding ◽  
Transmembrane Protein ◽  
Brain Regions ◽  
Morphological Data ◽  
Cell Populations ◽  
Male And Female ◽  
Female Mice

AbstractBackgroundIschemic stroke is an acquired brain injury with gender-dependent outcomes. A persistent obstacle in understanding the sex-specific neuroinflammatory contributions to ischemic brain injury is distinguishing between resident microglia and infiltrating macrophages—both phagocytes—and determining cell population-specific contributions to injury evolution and recovery processes. Our purpose was to identify microglial and macrophage populations regulated by ischemic stroke using morphology analysis and the presence of microglia transmembrane protein 119 (TMEM119). Second, we examined sex and menopause differences in microglia/macrophage cell populations after an ischemic stroke.MethodsMale and female, premenopausal and postmenopausal, mice underwent either 60 min of middle cerebral artery occlusion and 24 h of reperfusion or sham surgery. The accelerated ovarian failure model was used to model postmenopause. Brain tissue was collected to quantify the infarct area and for immunohistochemistry and western blot methods. Ionized calcium-binding adapter molecule, TMEM119, and confocal microscopy were used to analyze the microglia morphology and TMEM119 area in the ipsilateral brain regions. Western blot was used to quantify protein quantity.ResultsPost-stroke injury is increased in male and postmenopause female mice vs. premenopause female mice (p< 0.05) with differences primarily occurring in the caudal sections. After stroke, the microglia underwent a region, but not sex group, dependent transformation into less ramified cells (p< 0.0001). However, the number of phagocytic microglia was increased in distal ipsilateral regions of postmenopausal mice vs. the other sex groups (p< 0.05). The number of TMEM119-positive cells was decreased in proximity to the infarct (p< 0.0001) but without a sex group effect. Two key findings prevented distinguishing microglia from systemic macrophages. First, morphological data were not congruent with TMEM119 immunofluorescence data. Cells with severely decreased TMEM119 immunofluorescence were ramified, a distinguishing microglia characteristic. Second, whereas the TMEM119 immunofluorescence area decreased in proximity to the infarcted area, the TMEM119 protein quantity was unchanged in the ipsilateral hemisphere regions using western blot methods.ConclusionsOur findings suggest that TMEM119 is not a stable microglia marker in male and female mice in the context of ischemic stroke. Until TMEM119 function in the brain is elucidated, its use to distinguish between cell populations following brain injury with cell infiltration is cautioned.

scholarly journals Inhaled Nitric Oxide Reduces Secondary Brain Damage after Traumatic Brain Injury in Mice

2012 ◽  
Vol 33 (2) ◽  
pp. 311-318 ◽  
Author(s):  
Nicole A Terpolilli ◽  
Seong-Woong Kim ◽  
Serge C Thal ◽  
Wolfgang M Kuebler ◽  
Nikolaus Plesnila
Keyword(s):  
Nitric Oxide ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Brain Regions ◽  
Lesion Volume ◽  
Effective Treatment Option ◽  
Secondary Brain Damage ◽  
Edema Formation ◽  
Regional Ischemia

Ischemia, especially pericontusional ischemia, is one of the leading causes of secondary brain damage after traumatic brain injury (TBI). So far efforts to improve cerebral blood flow (CBF) after TBI were not successful because of various reasons. We previously showed that nitric oxide (NO) applied by inhalation after experimental ischemic stroke is transported to the brain and induces vasodilatation in hypoxic brain regions, thus improving regional ischemia, thereby improving brain damage and neurological outcome. As regional ischemia in the traumatic penumbra is a key mechanism determining secondary posttraumatic brain damage, the aim of the current study was to evaluate the effect of NO inhalation after experimental TBI. NO inhalation significantly improved CBF and reduced intracranial pressure after TBI in male C57 Bl/6 mice. Long-term application (24 hours NO inhalation) resulted in reduced lesion volume, reduced brain edema formation and less blood–brain barrier disruption, as well as improved neurological function. No adverse effects, e.g., on cerebral auto-regulation, systemic blood pressure, or oxidative damage were observed. NO inhalation might therefore be a safe and effective treatment option for TBI patients.

scholarly journals Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats

2019 ◽  
Vol 36 (11) ◽  
pp. 1890-1907 ◽  
Author(s):  
Pedro Andrade ◽  
Ivette Banuelos-Cabrera ◽  
Niina Lapinlampi ◽  
Tomi Paananen ◽  
Robert Ciszek ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Status Epilepticus ◽  
Brain Injury ◽  
Convulsive Status Epilepticus ◽  
Experimental Traumatic Brain Injury

scholarly journals Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiuyun Liu ◽  
Aylin Tekes ◽  
Jamie Perin ◽  
May W. Chen ◽  
Bruno P. Soares ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Brain Injury ◽  
Therapeutic Hypothermia ◽  
Near Infrared ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Volume Index ◽  
Arterial Blood ◽  
Blood Pressures ◽  
Ischemic Encephalopathy

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50–60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

scholarly journals The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Teena K. J. B. Gamage ◽  
Mhoyra Fraser
Keyword(s):  
Stem Cell ◽  
Brain Injury ◽  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Brain Structures ◽  
Developing Brain ◽  
Long Term Effects ◽  
Perinatal Brain Injury ◽  
Current Perspective ◽  
Promising Source

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

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