scholarly journals Modeling of Hypoxic Brain Injury through 3D Human Neural Organoids

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 234
Author(s):  
Min Soo Kim ◽  
Da-Hyun Kim ◽  
Hyun Kyoung Kang ◽  
Myung Geun Kook ◽  
Soon Won Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Neurodegenerative Diseases ◽  
Drug Screening ◽  
Human Cerebral Cortex ◽  
Hypoxic Injury ◽  
Hypoxic Brain Injury ◽  
Hypoxic Brain

Brain organoids have emerged as a novel model system for neural development, neurodegenerative diseases, and human-based drug screening. However, the heterogeneous nature and immature neuronal development of brain organoids generated from pluripotent stem cells pose challenges. Moreover, there are no previous reports of a three-dimensional (3D) hypoxic brain injury model generated from neural stem cells. Here, we generated self-organized 3D human neural organoids from adult dermal fibroblast-derived neural stem cells. Radial glial cells in these human neural organoids exhibited characteristics of the human cerebral cortex trend, including an inner (ventricular zone) and an outer layer (early and late cortical plate zones). These data suggest that neural organoids reflect the distinctive radial organization of the human cerebral cortex and allow for the study of neuronal proliferation and maturation. To utilize this 3D model, we subjected our neural organoids to hypoxic injury. We investigated neuronal damage and regeneration after hypoxic injury and reoxygenation. Interestingly, after hypoxic injury, reoxygenation restored neuronal cell proliferation but not neuronal maturation. This study suggests that human neural organoids generated from neural stem cells provide new opportunities for the development of drug screening platforms and personalized modeling of neurodegenerative diseases, including hypoxic brain injury.

scholarly journals Insights into the Biology and Therapeutic Applications of Neural Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Lachlan Harris ◽  
Oressia Zalucki ◽  
Michael Piper ◽  
Julian Ik-Tsen Heng
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Therapeutic Potential ◽  
Biological Significance ◽  
Adult Brain ◽  
Cognitive Capacity ◽  
Molecular Characteristics

The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the diversity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease.

Isolation of neural stem cells from damaged rat cerebral cortex after traumatic brain injury

Neuroreport ◽  
2005 ◽  
Vol 16 (15) ◽  
pp. 1687-1691 ◽  
Author(s):  
Tatsuki Itoh ◽  
Takao Satou ◽  
Shigeo Hashimoto ◽  
Hiroyuki Ito
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Cerebral Cortex ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Rat Cerebral Cortex

scholarly journals Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Ana G. Cristancho ◽  
Eric D. Marsh
Keyword(s):  
Dna Methylation ◽  
Brain Injury ◽  
Brain Development ◽  
In Utero ◽  
Hypoxic Injury ◽  
Neurodevelopmental Disease ◽  
Epigenetic Modifiers ◽  
Hypoxic Brain Injury ◽  
Hypoxic Brain

Abstract Background The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability. Main body Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury. Conclusions This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury.

scholarly journals Human fetal neural stem cell-derived astrocytes maintain glutamate transport after hypoxic injury in vitro

2021 ◽  
Author(s):  
Vadanya Shrivastava ◽  
Devanjan Dey ◽  
Chitra Mohinder Singh Singal ◽  
Paritosh Jaiswal ◽  
Ankit Singh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Brain Injury ◽  
Neural Stem Cell ◽  
Glutamate Uptake ◽  
Stem Cell Marker ◽  
Severe Hypoxia ◽  
Glutamate Excitotoxicity ◽  
Hypoxic Injury ◽  
Hypoxic Brain Injury ◽  
Hypoxic Brain

Astrocytes are the most abundant glial cells that play many critical roles in the central nervous system physiology including the uptake of excess glutamate from the synapse by Excitatory Amino Acid Transporters (EAATs). Among the EAATs, EAAT2 are predominantly functional, astrocyte-specific glutamate transporters in the forebrain. Hypoxic brain injury is a pathological phenomenon seen in various clinical conditions including stroke and neonatal hypoxic ischemic encephalopathy. Glutamate excitotoxicity is an important cause of neuronal cell death in disorders involving hypoxic brain injury. As findings from rodent models cannot always be reliably extrapolated to humans, we aimed to develop a homogenous population of primary human astrocytes to study the effect of hypoxic injury on astrocyte function, especially glutamate uptake. We successfully isolated, established and characterized cultures of human fetal neural stem cells (FNSCs) from aborted fetal brains. FNSCs were differentiated into astrocytes, and characterized by increased expression of the astrocyte marker, glial fibrillary acidic protein (GFAP), and a concomitant decrease in neural stem cell marker, Nestin. Differentiated astrocytes were exposed to various oxygen concentrations mimicking normoxia (20% and 6%), moderate and severe hypoxia (2% and 0.2% respectively). Interestingly, no change was observed in the expression of glutamate transporter, EAAT2 and glutamate uptake by astrocytes, even after exposure to hypoxia. Our novel model of human FNSC derived astrocytes exposed to hypoxic injury, establishes that astrocytes are able to maintain glutamate uptake even after exposure to severe hypoxia for 48 hours, and thus provides evidence for the neuroprotective role of astrocytes in hypoxic injury.

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