scholarly journals Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation After Experimental Traumatic Brain Injury

2017 ◽  
Author(s):  
Genevieve M. Sullivan ◽  
Regina C. Armstrong
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Signaling ◽  
Fluorescent Reporter

ABSTRACTNeural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined Sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato host mice demonstrated Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSC expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.

scholarly journals Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation after Experimental Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Genevieve M. Sullivan ◽  
Regina C. Armstrong
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Signaling ◽  
Fluorescent Reporter

Neural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribingShhorGli1after transplantation and/or TBI.Gli1transcription is an effective readout for canonical Shh signaling. InShhCreERT2;R26tdTomatomice,Shhwas primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results inGli1CreERT2;R26tdTomatomice demonstrated that Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSCs expressedShhin vivo but did not increaseGli1labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling viaGli1transcription.

scholarly journals Freshly Thawed Cryobanked Human Neural Stem Cells Engraft within Endogenous Neurogenic Niches and Restore Cognitive Function Following Chronic Traumatic Brain Injury

2020 ◽  
Author(s):  
Anna Badner ◽  
Emily K. Reinhardt ◽  
Theodore V. Nguyen ◽  
Nicole Midani ◽  
Andrew T. Marshall ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Spatial Learning ◽  
Risk Taking ◽  
Mechanisms Of Action ◽  
Human Neural Stem Cells ◽  
Risk Taking Behavior

AbstractHuman neural stem cells (hNSCs) have potential as a cell therapy following traumatic brain injury (TBI). While various studies have demonstrated the efficacy of NSCs from on-going culture, there is a significant gap in our understanding of freshly thawed cells from cryobanked stocks – a more clinically-relevant source. To address these shortfalls, the therapeutic potential of our previously validated Shef-6.0 human embryonic stem cell (hESC)-derived hNSC line was tested following long-term cryostorage and thawing prior to transplant. Immunodeficient athymic nude rats received a moderate unilateral controlled cortical impact (CCI) injury. At 4-weeks post-injury, 6×105 freshly thawed hNSCs were transplanted into six injection sites (2 ipsi- and 4 contra-lateral) with 53.4% of cells surviving three months post-transplant. Interestingly, most hNSCs were engrafted in the meninges and the lining of lateral ventricles, associated with high CXCR4 expression and a chemotactic response to SDF1alpha (CXCL12). While some expressed markers of neuron, astrocyte, and oligodendrocyte lineages, the majority remained progenitors, identified through doublecortin expression (78.1%). Importantly, transplantation resulted in improved spatial learning and memory in Morris water maze navigation and reduced risk-taking behavior in an elevated plus maze. Investigating potential mechanisms of action, we identified an increase in ipsilateral host hippocampus cornu ammonis (CA) neuron survival, contralateral dentate gyrus (DG) volume and DG neural progenitor morphology as well as a reduction in neuroinflammation. Together, these findings validate the potential of hNSCs to restore function after TBI and demonstrate that long-term bio-banking of cells and thawing aliquots prior to use may be suitable for clinical deployment.Significance StatementThere is no cure for chronic traumatic brain injury (TBI). While human neural stem cells (hNSCs) offer a potential treatment, no one has demonstrated efficacy of thawed hNSCs from long-term cryobanked stocks. Frozen aliquots are critical for multisite clinical trials, as this omission impacted the use of MSCs for graft versus host disease. This is the first study to demonstrate the efficacy of thawed hNSCs, while also providing support for novel mechanisms of action – linking meningeal and ventricular engraftment to reduced neuroinflammation and improved hippocampal neurogenesis. Importantly, these changes also led to clinically relevant effects on spatial learning/memory and risk-taking behavior. Together, this new understanding of hNSCs lays a foundation for future work and improved opportunities for patient care.

Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury

2006 ◽  
Vol 201 (2) ◽  
pp. 281-292 ◽  
Author(s):  
J GAO ◽  
D PROUGH ◽  
D MCADOO ◽  
J GRADY ◽  
M PARSLEY ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Cognitive Function ◽  
Neural Stem Cells

Activation of endogenous neural stem cells after traumatic brain injury

The Lancet ◽  
2014 ◽  
Vol 383 ◽  
pp. S18 ◽  
Author(s):  
Aminul Ahmed ◽  
Anan Shtaya ◽  
Malik Zaben ◽  
William Gray
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Endogenous Neural Stem Cells

scholarly journals Traumatic Brain Injury as a Disorder of Brain Connectivity

2016 ◽  
Vol 22 (2) ◽  
pp. 120-137 ◽  
Author(s):  
Jasmeet P. Hayes ◽  
Erin D. Bigler ◽  
Mieke Verfaellie
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Functional Connectivity ◽  
Negative Impact ◽  
Axonal Injury ◽  
Resting State Functional Connectivity ◽  
Post Injury ◽  
Recent Advances

AbstractObjectives:Recent advances in neuroimaging methodologies sensitive to axonal injury have made it possible to assess in vivo the extent of traumatic brain injury (TBI) -related disruption in neural structures and their connections. The objective of this paper is to review studies examining connectivity in TBI with an emphasis on structural and functional MRI methods that have proven to be valuable in uncovering neural abnormalities associated with this condition.Methods:We review studies that have examined white matter integrity in TBI of varying etiology and levels of severity, and consider how findings at different times post-injury may inform underlying mechanisms of post-injury progression and recovery. Moreover, in light of recent advances in neuroimaging methods to study the functional connectivity among brain regions that form integrated networks, we review TBI studies that use resting-state functional connectivity MRI methodology to examine neural networks disrupted by putative axonal injury.Results:The findings suggest that TBI is associated with altered structural and functional connectivity, characterized by decreased integrity of white matter pathways and imbalance and inefficiency of functional networks. These structural and functional alterations are often associated with neurocognitive dysfunction and poor functional outcomes.Conclusions:TBI has a negative impact on distributed brain networks that lead to behavioral disturbance. (JINS, 2016,22, 120–137)

Corpus Callosum Vasculature Predicts White Matter Microstructure Abnormalities after Pediatric Mild Traumatic Brain Injury

2019 ◽  
Vol 36 (1) ◽  
pp. 152-164 ◽  
Author(s):  
Kara M. Wendel ◽  
Jeong Bin Lee ◽  
Bethann M. Affeldt ◽  
Mary Hamer ◽  
Indira S. Harahap-Carrillo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Mild Traumatic Brain Injury ◽  
White Matter Microstructure

Stem Cell Studies in Traumatic Brain Injury

Neurotrauma ◽  
2018 ◽  
pp. 373-386
Author(s):  
Dong Sun
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Stem Cell ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Cell Transplantation ◽  
Survival Rates ◽  
Structural Repair ◽  
Potential Strategy ◽  
Endogenous Neural Stem Cells

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rates after TBI, there is no effective treatment to improve the neural structural repair and functional recovery of patients. Neural regeneration through neural stem cells, either by stimulating endogenous neural stem cells or by stem cell transplantation, has gained increasing attention as a potential strategy to repair and regenerate the injured brain. This chapter summarizes strategies that have been explored to enhance endogenous neural stem cells-mediated regeneration and recent developments in cell transplantation studies for post-TBI brain repair with varying types of cell sources.

scholarly journals Sonic Hedgehog Signaling Mediates Resveratrol to Increase Proliferation of Neural Stem Cells After Oxygen-Glucose Deprivation/Reoxygenation Injury in Vitro

2015 ◽  
Vol 35 (5) ◽  
pp. 2019-2032 ◽  
Author(s):  
Wei Cheng ◽  
Pingping Yu ◽  
Li Wang ◽  
Changbo Shen ◽  
Xiaosong Song ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Glucose Deprivation ◽  
Adult Brain ◽  
Immunocytochemical Staining ◽  
Oxygen Glucose Deprivation ◽  
Shh Signaling ◽  
Gli 1

Background/Aims: There is interest in drugs and rehabilitation methods to enhance neurogenesis and improve neurological function after brain injury or degeneration. Resveratrol may enhance hippocampal neurogenesis and improve hippocampal atrophy in chronic fatigue mice and prenatally stressed rats. However, its effect and mechanism of neurogenesis after stroke is less well understood. Sonic hedgehog (Shh) signaling is crucial for neurogenesis in the embryonic and adult brain, but relatively little is known about the role of Shh signaling in resveratrol-enhanced neurogenesis after stroke. Methods: Neural stem cells (NSCs) before oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were pretreated with resveratrol with or without cyclopamine. Survival and proliferation of NSCs was assessed by the CCK8 assay and BrdU immunocytochemical staining. The expressions and activity of signaling proteins and mRNAs were detected by immunocytochemistry, Western blotting, and RT-PCR analysis. Results: Resveratrol significantly increased NSCs survival and proliferation in a concentration-dependent manner after OGD/R injury in vitro. At the same time, the expression of Patched-1, Smoothened (Smo), and Gli-1 proteins and mRNAs was upregulated, and Gli-1 entered the nucleus, which was inhibited by cyclopamine, a Smo inhibitor. Conclusion: Shh signaling mediates resveratrol to increase NSCs proliferation after OGD/R injury in vitro.

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