Abstract WP115: Transplanted Induced Neural Stem Cells Differentiate and Integrate Into the Brain Parenchyma of Ischemic Stroke Pigs Leading to Improved Tissue Recovery

Studies in rodents have provided evidence that induced pluripotent stem cell derived neural stem cells (iNSCs) have a multifunctional role in stroke recovery. iNSCs mitigate tissue loss due to secondary injury, promote tissue recovery through angiogenesis, and differentiate into mature neural cell types resulting in recovery and replacement of lost and damaged brain tissue. However, many stroke therapies developed in the rodent have failed in clinical trials, suggesting that iNSC therapy should be tested in a more translatable large animal model such as the pig. The objective of this study was to assess the ability of iNSCs to differentiate into mature neural cell types and characterize the effects of iNSCs on brain tissue recovery utilizing non-invasive magnetic resonance imaging (MRI) and spectroscopy approaches in a pig model. Eight male landrace pigs underwent middle cerebral artery occlusion stroke surgery. After 5 days, 4 pigs received iNSC intraparenchymal injections and 4 pigs received vehicle only injections. Pigs underwent MRI assessment at 24 hrs post-stroke and 1, 4, and 12 wks post-injection, and brain tissues were collected 12 wks post-injection. At 12 wks post-injection, iNSC treated pigs showed significant improvement in white matter integrity with recovery of fractional anisotropy being 4-fold higher in treated pigs relative to non-treated pigs. Perfusion weighted imaging demonstrated significant improvement in cerebral blood volume (13%), time to peak (36%), and mean transit time (41%) in treated pigs at 12 wks post-injection vs. non-treated pigs. In addition, treated pigs showed significant improvement in neurometabolites NAA, Cr, and Cho at 12 wks post-injection relative to non-treated pigs. Gene expression analysis established significant increases in neurotrophic and angiogenic factors including BDNF and ANG1, respectively, in brain tissue of treated pigs vs. non-treated pigs suggesting potential modes of action. iNSCs were located in the brain parenchyma 12 wks post-injection, and the majority were positive for the mature neuronal marker NeuN. These results demonstrated that iNSCs are capable of neuronal differentiation and long term integration while promoting tissue recovery in a preclinical pig ischemic stroke model.

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Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽

10.3390/v13081468 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1468

Author(s):

Yashika S. Kamte ◽

Manisha N. Chandwani ◽

Alexa C. Michaels ◽

Lauren A. O’Donnell

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Viral Infections ◽

Wide Spectrum ◽

Cell Types ◽

Developmental Abnormalities ◽

Multipotent Progenitor Cells ◽

The Central Nervous System ◽

Simplex Virus ◽

The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

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DNA Methylation Abnormality and Brain Dysfunction of Neural Stem Cells Caused by Chronic Inflammation by Nanoparticle Exposure

Impact ◽

10.21820/23987073.2020.7.28 ◽

2020 ◽

Vol 2020 (7) ◽

pp. 28-30

Author(s):

Ken Tachibana

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neural Development ◽

Broad Class ◽

Cell Types ◽

Associate Professor ◽

Adult Brain ◽

Wide Range ◽

The Creation ◽

The Brain

The biological development of a human is an extremely complex and delicate process. It starts from fertilisation and continues until long after birth. The creation and development of the brain is particularly complicated and susceptible to disruptions to its progression. The primary cells responsible for the development of the brain are the neural stem cells. These are a broad class of cells that can differentiate into the wide range of cell types that form the adult brain. To achieve this complex process, different cells need to undergo a range of gene expression changes at the right time. This is delicate and its disturbance is a key cause of pathology in a wide range of diseases. There are many external factors that are known to disrupt neural development however, there are several common chemicals whose effects remain largely unknown. One such group are broadly described as nanoparticles. These are small particles that are being increasingly used by many industries as they can help in the creation of products with better properties. However, their effect on the environment and the human body – particularly that of a developing brain – have been largely unexamined. Associate Professor Ken Tachibana of the Division of Hygienic Chemistry, Sanyo-Onoda City University, Japan is researching the effects of nanoparticles on neural development.

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Spinal cord neural stem cells heterogeneity in postnatal development

STEMedicine ◽

10.37175/stemedicine.v1i1.19 ◽

2020 ◽

Vol 1 (1) ◽

pp. e19

Author(s):

Jelena Ban ◽

Miranda Mladinic

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Cell Types ◽

In Vitro Models ◽

Cell Potential ◽

Neurogenic Niche ◽

The Brain

Neural stem cells are capable of generating new neurons during development as well as in the adulthood and represent one of the most promising tools to replace lost or damaged neurons after injury or neurodegenerative disease. Unlike the brain, neurogenesis in the adult spinal cord is poorly explored and the comprehensive characterization of the cells that constitute stem cell neurogenic niche is still missing. Moreover, the terminology used to specify developmental and/or anatomical CNS regions, where neurogenesis in the spinal cord occurs, is not consensual and the analogy with the brain is often unclear. In this review, we will try to describe the heterogeneity of the stem cell types in the spinal cord ependymal zone, based on their origin and stem cell potential. We will also consider specific animal in vitro models that could be useful to identify “the right” stem cell candidate for cell replacement therapies.

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Stem cells in stroke management

Reviews in Clinical Gerontology ◽

10.1017/s0959259810000390 ◽

2010 ◽

Vol 21 (2) ◽

pp. 125-140

Author(s):

Keith W Muir

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tissue Regeneration ◽

Clinical Studies ◽

Cell Types ◽

Adult Brain ◽

Permanent Disability ◽

Ischaemic Injury ◽

Cell Therapies ◽

The Brain

SummaryStem cells are a potential means of tissue regeneration in the brain that hold promise for treatment of the large number of stroke survivors who have permanent disability. Animal studies with stem cells derived from many different sources indicate that cells can migrate to the site of ischaemic injury in the brain, and that some survive and differentiate into neurones and glia with evidence of electrical function. Cells additionally promote endogenous repair mechanisms, including mobilization of neural stem cells resident within the adult brain. Whether the behavioural benefits seen with stem cell administration in rodent models reflect enhanced endogenous recovery or tissue regeneration is unclear. Production of stem cells to clinical standards and in quantities required for clinical studies is technically challenging. To date only a handful of patients have been involved in preliminary clinical studies of cell therapies for stroke, and there are therefore insufficient data to draw conclusions about either safety or efficacy. Further trials with several cell types are ongoing or planned, including neural stem cells, and bone marrow-derived stem cells and endothelial progenitor cells.

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Three-dimensional cultured mesenchymal stem cells enhance repair of ischemic stroke through inhibition of microglia

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02416-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yuejiao Li ◽

Yankai Dong ◽

Ye Ran ◽

Yanan Zhang ◽

Boyao Wu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ischemic Stroke ◽

Proinflammatory Cytokines ◽

Infarct Volume ◽

Brain Lesion ◽

Three Dimensional ◽

Artery Occlusion ◽

Rna Seq ◽

The Brain

Abstract Background We show previously that three-dimensional (3D) spheroid cultured mesenchymal stem cells (MSCs) exhibit reduced cell size thus devoid of lung entrapment following intravenous (IV) infusion. In this study, we determined the therapeutic effect of 3D-cultured MSCs on ischemic stroke and investigated the mechanisms involved. Methods Rats underwent middle cerebral artery occlusion (MCAO) and reperfusion. 1 × 106 of 3D- or 2D-cultured MSCs, which were pre-labeled with GFP, were injected through the tail vain three and seven days after MCAO. Two days after infusion, MSC engraftment into the ischemic brain tissues was assessed by histological analysis for GFP-expressing cells, and infarct volume was determined by MRI. Microglia in the lesion were sorted and subjected to gene expressional analysis by RNA-seq. Results We found that infusion of 3D-cultured MSCs significantly reduced the infarct volume of the brain with increased engraftment of the cells into the ischemic tissue, compared to 2D-cultured MSCs. Accordingly, in the brain lesion of 3D MSC-treated animals, there were significantly reduced numbers of amoeboid microglia and decreased levels of proinflammatory cytokines, indicating attenuated activation of the microglia. RNA-seq of microglia derived from the lesions suggested that 3D-cultured MSCs decreased the response of microglia to the ischemic insult. Interestingly, we observed a decreased expression of mincle, a damage-associated molecular patterns (DAMPs) receptor, which induces the production of proinflammatory cytokines, suggestive of a potential mechanism in 3D MSC-mediated enhanced repair to ischemic stroke. Conclusions Our data indicate that 3D-cultured MSCs exhibit enhanced repair to ischemic stroke, probably through a suppression to ischemia-induced microglial activation.

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Protective effect of Saccharomyces cerevisiae in Rattus norvegicus Ischemic Stroke Model

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.01006 ◽

2021 ◽

pp. 5785-5789

Author(s):

Dedy Budi Kurniawan ◽

Mokhamad Fahmi Rizki Syaban ◽

Arinal Mufidah ◽

Muhammad Unzila Rafsi Zulfikri ◽

Wibi Riawan

Keyword(s):

Saccharomyces Cerevisiae ◽

Ischemic Stroke ◽

Brain Tissue ◽

Tissue Injury ◽

Intervention Group ◽

Positive Control ◽

Positive Control Group ◽

Control Group ◽

Hematopoietic Stem ◽

The Brain

Stroke is one of the leading causes of morbidity and mortality in all ages. Ischemic stroke activates excitotoxic glutamate cascade leading to brain tissue injury. Saccharomyces cerevisiae is a unicellular yeast widely found in nature. S. cerevisiae is neuroprotective and able to increase the differentiation of hematopoietic stem cells (HSCs) into neuronal cells. it may increase levels of neuroprotectant BDNF in the brain tissue, therefore increase the protection of neurons. BDNF may prevent glutamate-driven excitotoxicity by reducing glutamate levels. This study uses a randomized post-test only controlled group design. In this in vivo study, rodent models of ischemic stroke were divided into five groups comprising of the negative control group, positive control group, intervention group 1 (18mg/kgBW), intervention group 2 (36mg/kgBW) and intervention group 3 (72 mg/kgBW). Groups treated with Saccharomyces cerevisiae extract showed significantly increased BDNF levels in the brain tissue, and the expression of the glutamate level was significantly reduced (P <0.05) compared to the positive control group. Thus Saccharomyces cerevisiae has a promising potential to become a therapy against ischemic stroke disease. however further research is needed regarding the efficacy and toxicity of Saccharomyces cerevisiae.

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P50. Role of glioma produced CM1 in the brain tumor tropism of human neural stem cells

Differentiation ◽

10.1016/j.diff.2010.09.056 ◽

2010 ◽

Vol 80 ◽

pp. S33-S34

Author(s):

J. Jeon ◽

S. Cho ◽

K. Cho ◽

Y. Lee ◽

M. Lee

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Neural Stem Cells ◽

Human Neural Stem Cells ◽

Tumor Tropism ◽

The Brain

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Integrated Patterning Programs During Drosophila Development Generate the Diversity of Neurons and Control Their Mature Properties

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-102120-014813 ◽

2021 ◽

Vol 44 (1) ◽

Author(s):

Anthony M. Rossi ◽

Shadi Jafari ◽

Claude Desplan

Keyword(s):

Stem Cells ◽

Nervous System ◽

Neural Stem Cells ◽

Cell Types ◽

Annual Review ◽

Publication Date ◽

Temporal Patterning ◽

Long Time ◽

Neuronal Types ◽

And Control

During the approximately 5 days of Drosophila neurogenesis (late embryogenesis to the beginning of pupation), a limited number of neural stem cells produce approximately 200,000 neurons comprising hundreds of cell types. To build a functional nervous system, neuronal types need to be produced in the proper places, appropriate numbers, and correct times. We discuss how neural stem cells (neuroblasts) obtain so-called area codes for their positions in the nervous system (spatial patterning) and how they keep time to sequentially produce neurons with unique fates (temporal patterning). We focus on specific examples that demonstrate how a relatively simple patterning system (Notch) can be used reiteratively to generate different neuronal types. We also speculate on how different modes of temporal patterning that operate over short versus long time periods might be linked. We end by discussing how specification programs are integrated and lead to the terminal features of different neuronal types. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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SCIDOT-22. INTRACEREBROVENTRICULAR DELIVERY OF TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS FOR TREATMENT OF BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noz175.1158 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi276-vi276

Author(s):

Wulin Jiang ◽

Alison Mercer-Smith ◽

Juli Bago ◽

Simon Khagi ◽

Carey Anders ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Brain Metastases ◽

Neural Stem Cells ◽

Tumor Homing ◽

Migration Assays ◽

Induced Neural Stem Cells ◽

First Time ◽

The Brain

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to target and eradicate metastases. We have developed genetically-engineered induced neural stem cells (hiNSCs) derived from human fibroblasts that selectively home to tumors and release the cytotoxic protein TRAIL. Building on these results, we explored the efficacy of hiNSC therapy delivered via intracerebroventricular (ICV) injections for the treatment of metastatic foci in the brain for the first time. METHODS We performed in vitro efficacy and migration assays in conjunction with in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the tumor. The migration and persistence of hiNSCs were investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescence of the tumor. RESULTS/ CONCLUSION Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. In vitro migration assays showed significant directional migration toward both lung and breast cancer cells within 4 days. ICV-administered hiNSC serial imaging shows that cells persisted for >1 week in the brain. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs suppressed the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.

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Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

International Journal of Molecular Sciences ◽

10.3390/ijms20020455 ◽

2019 ◽

Vol 20 (2) ◽

pp. 455 ◽

Cited By ~ 3

Author(s):

Felix Beyer ◽

Iria Samper Agrelo ◽

Patrick Küry

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Ex Vivo ◽

Meta Analysis ◽

Cell Types ◽

Adult Brain ◽

Repair Capacity ◽

Cell Fate Decisions ◽

Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

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