Physical therapy exerts sub-additive and suppressive effects on intracerebral neural stem cell implantation in a rat model of stroke

2021 ◽  
pp. 0271678X2110629
Author(s):  
Harmanvir Ghuman ◽  
Nikhita Perry ◽  
Lauren Grice ◽  
Madeline Gerwig ◽  
Jeffrey Moorhead ◽  
...  
Keyword(s):  
Stem Cell ◽  
Physical Therapy ◽  
Neural Stem Cell ◽  
Therapeutic Effects ◽  
Clinical Grade ◽  
Behavioral Testing ◽  
The Impact ◽  
Post Implantation ◽  
Sensory Neglect ◽  
Cell Implantation

Intracerebral cell therapy (CT) is emerging as a new therapeutic paradigm for stroke. However, the impact of physical therapy (PT) on implanted cells and their ability to promote recovery remains poorly understood. To address this translational issue, a clinical-grade neural stem cell (NSC) line was implanted into peri-infarct tissue using MRI-defined injection sites, two weeks after stroke. PT in the form of aerobic exercise (AE) was administered 5 × per week post-implantation using a paradigm commonly applied in patients with stroke. A combined AE and CT exerted sub-additive therapeutic effects on sensory neglect, whereas AE suppressed CT effects on motor integration and grip strength. Behavioral testing emerged as a potentially major component for task integration. It is expected that this study will guide and inform the incorporation of PT in the design of clinical trials evaluating intraparenchymal NSCs implantation for stroke.

scholarly journals Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2)

2020 ◽  
Vol 91 (4) ◽  
pp. 396-401 ◽  
Author(s):  
Keith W Muir ◽  
Diederik Bulters ◽  
Mark Willmot ◽  
Nikola Sprigg ◽  
Anand Dixit ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Multicentre Study ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Upper Limb ◽  
Limb Movement ◽  
Human Neural Stem Cells ◽  
Human Neural Stem Cell ◽  
Cell Implantation

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

scholarly journals The Impact of Cannabinoid Exposure on Glucocorticoid Receptor Signaling in Neural Stem Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A73-A73
Author(s):  
Nikki Gill ◽  
Suban Burale ◽  
Neerupma Silswal ◽  
Donald Benedict DeFranco ◽  
Paula Monaghan-Nichols
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Preterm Birth ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Cannabis Use ◽  
Biological Impact ◽  
Proliferation And Differentiation ◽  
The Impact

Abstract Preterm birth-birth before 37 weeks of pregnancy-can cause many short- and long-term complications in newborns, including respiratory distress syndrome (RDS). RDS results from incomplete lung development and a surfactant deficiency, and it is a major factor of pre-term mortality. Synthetic glucocorticoids (sGCs) such as Betamethasone or Dexamethasone (Beta, Dex) are administered prenatally to women at risk of pre-term birth to prevent preterm complications. While sGCs are known to improve outcome, they also cause alterations in brain development and neural stem cell biology that are associated with long-term neurological defects. One common recreational drug used during pregnancy is cannabis. Some of the active components of cannabis include cannabinoids, which interact with the endocannabinoid receptor pathway in cells. Cannabinoids have been shown to induce proliferation and differentiation of embryonic neural stem cells (NSCs). We hypothesized that maternal cannabis use activates cannabinoid signaling pathways and leads to changes in glucocorticoid signaling in the developing brain. The purpose of this study was to determine whether cannabis use leads to a better or worse neurological outcome for children born pre-term and treated with sGCs for RDS. Neural stem cell neurospheres (NSCs) were isolated from the cerebral cortex of mice and treated with Vehicle (ethanol), Dex, cannabinoid receptor agonist WIN-55,212-2 (Win), or a combination WinDex. The transcriptional profile induced by exposure to Vehicle, Dex, and WinDex RNA were analyzed using microarray analyses examining the complete expressed genome. Gene Chip profiles indicated that both glucocorticoids and cannabinoids induce distinct transcriptional responses in E14.5 NSCs. The genes involved in proliferation-including S100a11, Jun, and Bex2-were repressed by Dex whereas WinDex rescued some of these expression profiles. Some genes encoding microRNA that inhibit our top target coding genes implicated in proliferation showed a greater induction by Dex compared to WinDex. Quantitative Polymerase Chain Reaction (qPCR) was performed to validate our genes of interest, including Adm, which has been shown to induce neural stem cell proliferation and differentiation. The biological impact of Winn on Dex-induced changes in NSC function were examined by in-vitro proliferation and differentiation studies using antibodies to Tuj1 (neurons), GFAP (glia), and CNPase (immature oligodendrocytes). The experiments indicate that Dex increased neuronal and oligodendrocyte differentiation, while WinDex appeared to reverse this phenotype in neurons. These studies suggest that cannabis use during pregnancy may limit the biological impact sGCs for preterm birth and lead to distinct cellular responses.

scholarly journals Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice

2016 ◽  
Vol 36 (12) ◽  
pp. 2134-2145 ◽  
Author(s):  
Takuma Wakai ◽  
Purnima Narasimhan ◽  
Hiroyuki Sakata ◽  
Eric Wang ◽  
Hideyuki Yoshioka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Intracerebral Hemorrhage ◽  
Neural Stem Cells ◽  
Cell Survival ◽  
Neural Stem Cell ◽  
Hypoxic Preconditioning ◽  
Neurological Deficits ◽  
Therapeutic Effects ◽  
Cell Recovery

Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient

2014 ◽  
Vol 21 (4) ◽  
pp. 618-622 ◽  
Author(s):  
Brian J. Dlouhy ◽  
Olatilewa Awe ◽  
Rajesh C. Rao ◽  
Patricia A. Kirby ◽  
Patrick W. Hitchon
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Neural Stem Cell ◽  
Cellular Growth ◽  
Mucosal Cell ◽  
Intramedullary Spinal Cord ◽  
Cord Injury ◽  
Cell Implantation

Over the last decade, human cell transplantation and neural stem cell trials have examined the feasibility and safety of these potential therapies for treatment of a variety of neurological disorders. However, significant safety concerns have surrounded these trials due to the possibility of ectopic, uncontrolled cellular growth and tumor formation. The authors present the case of an 18-year-old woman who sustained a complete spinal cord injury at T10–11. Three years after injury, she remained paraplegic and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an intramedullary spinal cord mass at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years.

scholarly journals Neural Stem Cells for Early Intervention of Ischemic Stroke: Neural Stem Cell Therapy for Early Phase Ischemic Stroke

2021 ◽  
Vol 22 (14) ◽  
pp. 7703
Author(s):  
Milton H. Hamblin ◽  
Jean-Pyo Lee
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Neural Stem Cell ◽  
Stem Cell Therapy ◽  
Treatment Time ◽  
Time Window ◽  
Early Stage ◽  
Neurovascular Injury ◽  
The Impact

Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.

scholarly journals The Impact of Neural Stem Cell Biology on CNS Carcinogenesis and Tumor Types

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
K. M. Kurian
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Cell Biology ◽  
The Body ◽  
Proliferative Potential ◽  
Stem Cell Biology ◽  
Tumor Types ◽  
The Impact ◽  
The Brain

The incidence of gliomas is on the increase, according to epidemiological data. This increase is a conundrum because the brain is in a privileged protected site behind the blood-brain barrier, and therefore partially buffered from environmental factors. In addition the brain also has a very low proliferative potential compared with other parts of the body. Recent advances in neural stem cell biology have impacted on our understanding of CNS carcinogenesis and tumor types. This article considers the cancer stem cell theory with regard to CNS cancers, whether CNS tumors arise from human neural stem cells and whether glioma stem cells can be reprogrammed.

scholarly journals Cereblon-Based Small-Molecule Compounds to Control Neural Stem Cell Proliferation in Regenerative Medicine

2021 ◽  
Vol 9 ◽  
Author(s):  
Tomomi Sato ◽  
Takumi Ito ◽  
Hiroshi Handa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Brain Size ◽  
Therapeutic Effects ◽  
Sedative Drug

Thalidomide, a sedative drug that was once excluded from the market owing to its teratogenic properties, was later found to be effective in treating multiple myeloma. We had previously demonstrated that cereblon (CRBN) is the target of thalidomide embryopathy and acts as a substrate receptor for the E3 ubiquitin ligase complex, Cullin-Ring ligase 4 (CRL4CRBN) in zebrafish and chicks. CRBN was originally identified as a gene responsible for mild intellectual disability in humans. Fetuses exposed to thalidomide in early pregnancy were at risk of neurodevelopmental disorders such as autism, suggesting that CRBN is involved in prenatal brain development. Recently, we found that CRBN controls the proliferation of neural stem cells in the developing zebrafish brain, leading to changes in brain size. Our findings imply that CRBN is involved in neural stem cell growth in humans. Accumulating evidence shows that CRBN is essential not only for the teratogenic effects but also for the therapeutic effects of thalidomide. This review summarizes recent progress in thalidomide and CRBN research, focusing on the teratogenic and therapeutic effects. Investigation of the molecular mechanisms underlying the therapeutic effects of thalidomide and its derivatives, CRBN E3 ligase modulators (CELMoDs), reveals that these modulators provide CRBN the ability to recognize neosubstrates depending on their structure. Understanding the therapeutic effects leads to the development of a novel technology called CRBN-based proteolysis-targeting chimeras (PROTACs) for target protein knockdown. These studies raise the possibility that CRBN-based small-molecule compounds regulating the proliferation of neural stem cells may be developed for application in regenerative medicine.

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