scholarly journals Hydrogen Sulfide as a Factor of Neuroprotection during the Constitutive and Reparative Neurogenesis in Fish Brain

2020 ◽  
Author(s):  
Evgeniya V. Pushchina ◽  
Anatoly A. Varaksin ◽  
Dmitry K. Obukhov
Keyword(s):  
Radial Glia ◽  
Fold Increase ◽  
Eye Injury ◽  
Post Injury ◽  
Cell Complexes ◽  
Reparative Neurogenesis ◽  
Neuroepithelial Cells ◽  
Simultaneous Decrease ◽  
Subsequent Activation ◽  
Traumatic Damage

The H2S-producing systems were studied in trout telencephalon, tectum, and cerebellum at 1 week after eye injury. The results of ELISA analysis have shown a 1.7-fold increase in the CBS expression at 1 week post-injury, as compared to the intact trout. In the ventricular and subventricular regions of trout telencephalon, CBS+ cells, as well as neuroepithelial and glial types, were detected. As a result of injury, the number of CBS+ neuroepithelial cells in the pallial and subpallial periventricular regions of the telencephalon increases. In the tectum, a traumatic damage leads to an increase in the CBS expression in radial glia with a simultaneous decrease in the number of CBS immunopositive neuroepithelial cells detected in intact animals. In the cerebellum, we revealed neuroglial interrelations, in which H2S is probably released from the astrocyte-like cells with subsequent activation of the neuronal NMDA receptors. The organization of the H2S-producing cell complexes suggests that the amount of glutamate produced in the trout cerebellum and its reuptake is controlled with the involvement of astrocyte-like cells, reducing its excitotoxicity. We believe that the increase in the number of H2S-producing cells constitutes a response to oxidative stress, and the overproduction of H2S neutralizes the reactive oxygen species.

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

scholarly journals Differential Regenerative Capacity of the Optic Tectum of Adult Medaka and Zebrafish

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuki Shimizu ◽  
Takashi Kawasaki
Keyword(s):  
Optic Tectum ◽  
Radial Glia ◽  
Stab Wound ◽  
Brain Structures ◽  
Post Injury ◽  
Regenerative Capacity ◽  
Injured Area ◽  
Brain Regeneration ◽  
The Central Nervous System ◽  
Regenerative Ability

Zebrafish have superior regenerative capacity in the central nervous system (CNS) compared to mammals. In contrast, medaka were shown to have low regenerative capacity in the adult heart and larval retina, despite the well-documented high tissue regenerative ability of teleosts. Nevertheless, medaka and zebrafish share similar brain structures and biological features to those of mammals. Hence, this study aimed to compare the neural stem cell (NSC) responses and regenerative capacity in the optic tectum of adult medaka and zebrafish after stab wound injury. Limited neuronal differentiation was observed in the injured medaka, though the proliferation of radial glia (RG) was induced in response to tectum injury. Moreover, the expression of the pro-regenerative transcriptional factors ascl1a and oct4 was not enhanced in the injured medaka, unlike in zebrafish, whereas expression of sox2 and stat3 was upregulated in both fish models. Of note, glial scar-like structures composed of GFAP+ radial fibers were observed in the injured area of medaka at 14 days post injury (dpi). Altogether, these findings suggest that the adult medaka brain has low regenerative capacity with limited neuronal generation and scar formation. Hence, medaka represent an attractive model for investigating and evaluating critical factors for brain regeneration.

Abstract 15142: Endogenous Cardiac Stem Cells’ Activation in Response to Injury Potentiates Their Regenerative Ability

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Andrew J Smith ◽  
Iolanda Aquila ◽  
Beverley J Henning ◽  
Mariangela Scalise ◽  
Bernardo Nadal-Ginard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Injury ◽  
Fold Increase ◽  
Cardiac Stem Cells ◽  
Post Injury ◽  
Activated State ◽  
Potential Benefits ◽  
Therapeutic Avenue

The identification of resident, endogenous cardiac stem cells (eCSCs) has re-shaped our understanding of cardiac cellular physiology, while offering a significant potential therapeutic avenue. The biology of these cells must be better understood to harness their potential benefits. We used an acute dose (s.c.; 5mgkg-1) of isoproterenol (ISO) to induce diffuse cardiac injury, with associated eCSC activation, in rats. As peak eCSC activation was at 24 hours post ISO-injury, c-kitpos eCSCs were isolated, characterised and their potential for growth and regenerative potential was assessed in vitro and in vivo, respectively. Activated eCSCs showed increased cell cycling activity (51+1% in S- or G2/M phases vs. 9+2% of quiescent), Ki67 expression (56+7% vs. 10+1%) and TERT expression (14-fold increase vs. quiescent). When directly harvested in culture, activated eCSCs showed augmented proliferation, clonogenicity and cardiosphere formation compared to quiescent eCSCs. Activated eCSCs showed increases in expression of numerous growth factors, particularly HGF, IGF-1, TGF-β, periostin, PDGF-AA and VEGF-A. Furthermore, significant alterations were found in the miRnome, notably increased miR-146b and -221, and decreased miR-192 and -351. ISO+5FU was administrated to mice to induce a model of chronic dilated cardiomyopathy, which is characterized by the ablation of eCSCs and the absence of cardiomyocyte replenishment. In these mice with chronic heart failure, freshly isolated quiescent eCSCs or activated eCSCs (2d post-ISO) were injected through the tail vein. 28 days after injection, activated but not quiescent eCSCs re-populated the resident CSC pool, promoted robust new cardiomyocyte formation and improved cardiac function when compared to saline-treated mice. Dual-labelling with BrdU and EdU at selected stages after ISO injury determined that activated eCSCs returned to a quiescent level by 10 weeks post-injury. In conclusion, CSCs rapidly switch from a quiescent to an activated state to match the myocardial needs for myocyte replacement after injury and then spontaneously go back to quiescence. Harnessing the molecules regulating this process may open up future novel approaches for effective myocardial regeneration.

scholarly journals Delta-Notch Signaling: The Long and The Short of a Neuron’s Influence on Progenitor Fates

2020 ◽  
Vol 8 (2) ◽  
pp. 8 ◽  
Author(s):  
Rachel Moore ◽  
Paula Alexandre
Keyword(s):  
Progenitor Cell ◽  
Radial Glia ◽  
Notch Signalling ◽  
Neural Progenitors ◽  
Cell Fates ◽  
Basal Surface ◽  
Neuroepithelial Cells ◽  
Mantle Layer ◽  
The Central Nervous System ◽  
Radial Glial

Maintenance of the neural progenitor pool during embryonic development is essential to promote growth of the central nervous system (CNS). The CNS is initially formed by tightly compacted proliferative neuroepithelial cells that later acquire radial glial characteristics and continue to divide at the ventricular (apical) and pial (basal) surface of the neuroepithelium to generate neurons. While neural progenitors such as neuroepithelial cells and apical radial glia form strong connections with their neighbours at the apical and basal surfaces of the neuroepithelium, neurons usually form the mantle layer at the basal surface. This review will discuss the existing evidence that supports a role for neurons, from early stages of differentiation, in promoting progenitor cell fates in the vertebrates CNS, maintaining tissue homeostasis and regulating spatiotemporal patterning of neuronal differentiation through Delta-Notch signalling.

scholarly journals Examining potential side effects of therapeutic hypothermia in experimental intracerebral hemorrhage

2016 ◽  
Vol 37 (8) ◽  
pp. 2975-2986 ◽  
Author(s):  
Shannon Wowk ◽  
Kelly J Fagan ◽  
Yonglie Ma ◽  
Helen Nichol ◽  
Frederick Colbourne
Keyword(s):  
Intracerebral Hemorrhage ◽  
Therapeutic Hypothermia ◽  
Fold Increase ◽  
Inflammatory Cells ◽  
Heme Iron ◽  
Whole Body ◽  
Hematoma Volume ◽  
Post Injury ◽  
X Ray ◽  
Non Heme Iron

Studies treating intracerebral hemorrhage (ICH) with therapeutic hypothermia (TH) have shown inconsistent benefits. We hypothesized that TH’s anti-inflammatory effects may be responsible as inflammatory cells are essential for removing degrading erythrocytes. Here, we subjected rats to a collagenase-induced striatal ICH followed by whole-body TH (∼33℃ for 11–72 h) or normothermia. We used X-ray fluorescence imaging to spatially quantify total and peri-hematoma iron three days post-injury. At three and seven days, we measured non-heme iron levels. Finally, hematoma volume was quantified on one, three, and seven days. In the injured hemisphere, total iron levels were elevated ( p < 0.001) with iron increasing in the peri-hematoma region ( p = 0.007). Non-heme iron increased from three to seven days (p < 0.001). TH had no effect on any measure of iron ( p ≥ 0.479). At one and three days, TH did not affect hematoma volume ( p ≥ 0.264); however, at seven days there was a four-fold increase in hematoma volume in 40% of treated animals ( p = 0.032). Thus, even when TH does not interfere with initial increases in total and non-heme iron or its containment, TH can cause re-bleeding post-treatment. This serious complication could partly account for the intermittent protection previously observed. This also raises serious concerns for clinical usage of TH for ICH.

scholarly journals Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury

2019 ◽  
Author(s):  
Kaytlyn A Gerbin ◽  
Katie A Mitzelfelt ◽  
Xuan Guan ◽  
Amy M Martinson ◽  
Charles E Murry
Keyword(s):  
Myocardial Infarction ◽  
Heart Function ◽  
Fold Increase ◽  
Post Injury ◽  
Graft Size ◽  
Cell Dose ◽  
Current Cell ◽  
Functional Benefit ◽  
3D Presentation

ABSTRACTCurrent cell transplantation techniques are hindered by small graft size, requiring high cell doses to achieve therapeutic cardiac remuscularization. Enhancing the proliferation of transplanted human stem cell-derived cardiomyocytes (hESC-CMs) could address this, allowing an otherwise subtherapeutic cell dose to prevent disease progression after myocardial infarction. Here, we designed a hydrogel that activates Notch signaling through 3D presentation of the Notch ligand Delta-1 to use as an injectate for transplanting hESC-CMs into the infarcted rat myocardium. After four weeks, hESC-CM proliferation increased 2-fold and resulted in a 3-fold increase in graft size with the Delta-1 hydrogel compared to controls. To stringently test the effect of Notch-mediated graft expansion on long-term heart function, a normally subtherapeutic dose of hESC-CMs was implanted into the infarcted myocardium and cardiac function was evaluated by echocardiography. Transplantation of the Delta-1 hydrogel + hESC-CMs augmented heart function and was significantly higher at three months compared to controls. Graft size and hESC-CM proliferation were also increased at three months post-implantation. Collectively, these results demonstrate the therapeutic approach of a Delta-1 functionalized hydrogel to reduce the cell dose required to achieve functional benefit after myocardial infarction by enhancing hESC-CM graft size and proliferation.

Abstract 251: Neuregulin Administration Stimulates Cardiomyocyte Proliferation In Neonatal Mice And In Myocardium From Human Infants

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Brian Polizzotti ◽  
Balakrishnan Ganapathy ◽  
Stuart Walsh ◽  
Sangita Choudhury ◽  
David Bennett ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heart Disease ◽  
Unmet Need ◽  
Fold Increase ◽  
Scar Formation ◽  
Cardiomyocyte Proliferation ◽  
Myocardial Repair ◽  
Post Injury ◽  
Human Infants ◽  
Neonatal Mice

Background: Regenerative strategies have the potential to transform heart failure therapies. Cell transplantation strategies have shown effectiveness and safety in clinical trials. A complementary strategy is based on directly stimulating the proliferation of endogenous cardiomyocytes. We have demonstrated that administration of the growth factor neuregulin (rNRG1), which has passed phase 2 testing, stimulates cardiomyocyte proliferation and improves myocardial repair in adult animal models. Since cardiomyocyte proliferation is active during myocardial growth, we hypothesized that NRG1 may be more effective in growing animals and humans. Methods: We developed a myocardial injury model (cryoinjury) in neonatal mice that recapitulates scar formation seen in infants with congenital heart disease (CHD). In contrast with ligation of the left anterior descending coronary artery (LAD), cryoinjury reduced cardiomyocyte cell cycle activity. We used this model to evaluate the effectiveness of rNRG1 administration. To assess the ability of rNRG1 to stimulate human cardiomyocyte proliferation, we developed an organotypic culture system for myocardium from infants with CHD. Results: Administration of NRG1 resulted in a 2-fold increase in cardiomyocyte cell cycle activity at 10 days post injury (dpi). After neonatal cryoinjury in mice, administration of rNRG1 from birth to 30 days of life significantly improved the ejection fraction, which was sustained for 30 days after the cessation of rNRG1 administration. In contrast, administration of NRG1 four to 34 days after cryoinjury transiently reduced scar formation, and transiently improved myocardial structure and function. In myocardium from infants with Tetralogy of Fallot (ToF) less than 6 months of age (n = 6), rNRG1 induced cardiomyocyte proliferation. Conclusions: These results indicate that stimulating cardiomyocyte proliferation may be clinically effective in human infants with heart disease, a population in whom a significant and unmet need exists.

scholarly journals N-arachidonoyl-L-serine (AraS) Possesses Proneurogenic Properties in Vitro and in Vivo after Traumatic Brain Injury

2013 ◽  
Vol 33 (8) ◽  
pp. 1242-1250 ◽  
Author(s):  
Ayelet Cohen-Yeshurun ◽  
Dafna Willner ◽  
Victoria Trembovler ◽  
Alexander Alexandrovich ◽  
Raphael Mechoulam ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cannabinoid Receptor ◽  
Fold Increase ◽  
Lesion Volume ◽  
Post Injury ◽  
Neuroprotective Effects ◽  
Neurobehavioral Function

N-arachidonoyl-L-serine (AraS) is a novel neuroprotective endocannabinoid. We aimed to test the effects of exogenous AraS on neurogenesis after traumatic brain injury (TBI). The effects of AraS on neural progenitor cells (NPC) proliferation, survival, and differentiation were examined in vitro. Next, mice underwent TBI and were treated with AraS or vehicle. Lesion volumes and clinical outcome were evaluated and the effects on neurogenesis were tested using immunohistochemistry. Treatment with AraS led to a dose-dependent increase in neurosphere size without affecting cell survival. These effects were partially reversed by CB1, CB2, or TRPV1 antagonists. AraS significantly reduced the differentiation of NPC in vitro to astrocytes or neurons and led to a 2.5-fold increase in expression of the NPC marker nestin. Similar effects were observed in vivo in mice treated with AraS 7 days after TBI. These effects were accompanied by a reduction in lesion volume and an improvement in neurobehavioral function compared with controls. AraS increases proliferation of NPCs in vitro in cannabinoid-receptor-mediated mechanisms and maintains NPC in an undifferentiated state in vitro and in vivo. Moreover, although given at 7 days post injury, these effects are associated with significant neuroprotective effects leading to an improvement in neurobehavioral functions.

scholarly journals Dynamics of clusterin protein expression in the brain and plasma following experimental traumatic brain injury

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shalini Das Gupta ◽  
Anssi Lipponen ◽  
Kaisa M. A. Paldanius ◽  
Noora Puhakka ◽  
Asla Pitkänen
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Expression ◽  
Fold Increase ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Post Injury ◽  
Fluid Percussion Injury ◽  
Clusterin Protein ◽  
The Brain

AbstractProgress in the preclinical and clinical development of neuroprotective and antiepileptogenic treatments for traumatic brain injury (TBI) necessitates the discovery of prognostic biomarkers for post-injury outcome. Our previous mRNA-seq data revealed a 1.8–2.5 fold increase in clusterin mRNA expression in lesioned brain areas in rats with lateral fluid-percussion injury (FPI)-induced TBI. On this basis, we hypothesized that TBI leads to increases in the brain levels of clusterin protein, and consequently, increased plasma clusterin levels. For evaluation, we induced TBI in adult male Sprague-Dawley rats (n = 80) by lateral FPI. We validated our mRNA-seq findings with RT-qPCR, confirming increased clusterin mRNA levels in the perilesional cortex (FC 3.3, p < 0.01) and ipsilateral thalamus (FC 2.4, p < 0.05) at 3 months post-TBI. Immunohistochemistry revealed a marked increase in extracellular clusterin protein expression in the perilesional cortex and ipsilateral hippocampus (7d to 1 month post-TBI), and ipsilateral thalamus (14d to 12 months post-TBI). In the thalamus, punctate immunoreactivity was most intense around activated microglia and mitochondria. Enzyme-linked immunoassays indicated that an acute 15% reduction, rather than an increase in plasma clusterin levels differentiated animals with TBI from sham-operated controls (AUC 0.851, p < 0.05). Our findings suggest that plasma clusterin is a candidate biomarker for acute TBI diagnosis.

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