scholarly journals The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

2021 ◽  
Vol 15 ◽  
Author(s):  
Lisiane O. Porciúncula ◽  
Livia Goto-Silva ◽  
Pitia F. Ledur ◽  
Stevens K. Rehen
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Functional Activity ◽  
Network Formation ◽  
Disease Modeling ◽  
Morphological Data ◽  
Neural Cells ◽  
Normal Brain ◽  
Human Brain Tissue ◽  
Cell Repertoire

Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.

scholarly journals Trace elements during primordial plexiform network formation in human cerebral organoids

2016 ◽  
Author(s):  
Rafaela C Sartore ◽  
Simone C Cardoso ◽  
Yuri V Lages ◽  
Julia M Paraguassu ◽  
Rodrigo F Madeiro da Costa ◽  
...  
Keyword(s):  
Trace Elements ◽  
Human Brain ◽  
Pluripotent Stem Cells ◽  
Cell Biology ◽  
Network Formation ◽  
Biological Processes ◽  
Human Brain Tissue ◽  
Human Brain Development ◽  
Calcium Iron ◽  
Human Telencephalon

Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon development. In the present work, we exposed cerebral organoids derived from human pluripotent stem cells to synchrotron radiation in order to measure how biologically valuable micronutrients are incorporated and distributed in the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves calcium, iron, phosphorus, potassium, sulfur, and zinc. Local trends in concentrations suggest a switch from passive to actively mediated transport across cell membranes. Finally, correlational analysis for pairs of elements shows spatially conserved patterns, suggesting they may physically associate, be stored in similar compartments or used in related biological processes. These findings might reflect which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood.

scholarly journals Challenges in Modeling Human Neural Circuit Formation via Brain Organoid Technology

2020 ◽  
Vol 14 ◽  
Author(s):  
Takeshi K. Matsui ◽  
Yuichiro Tsuru ◽  
Ken-ichiro Kuwako
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neural Circuit ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Neural Lineage ◽  
Human Brain Development ◽  
Brain Organoid ◽  
Circuit Formation

Human brain organoids are three-dimensional self-organizing tissues induced from pluripotent cells that recapitulate some aspects of early development and some of the early structure of the human brain in vitro. Brain organoids consist of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes and oligodendrocytes. Additionally, brain organoids contain fluid-filled ventricle-like structures surrounded by a ventricular/subventricular (VZ/SVZ) zone-like layer of neural stem cells (NSCs). These NSCs give rise to neurons, which form multiple outer layers. Since these structures resemble some aspects of structural arrangements in the developing human brain, organoid technology has attracted great interest in the research fields of human brain development and disease modeling. Developmental brain disorders have been intensely studied through the use of human brain organoids. Relatively early steps in human brain development, such as differentiation and migration, have also been studied. However, research on neural circuit formation with brain organoids has just recently began. In this review, we summarize the current challenges in studying neural circuit formation with organoids and discuss future perspectives.

scholarly journals DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan

2020 ◽  
Vol 7 (1) ◽  
pp. e537
Author(s):  
Kathleen E. Langbehn ◽  
Zoe Carlson-Stadler ◽  
Ellen van der Plas ◽  
Marco M. Hefti ◽  
Jeffrey D. Dawson ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Brain Tissue ◽  
Myotonic Dystrophy ◽  
Messenger Rna ◽  
Trinucleotide Repeat ◽  
Expression Patterns ◽  
Data Sets ◽  
Linear Regression Models ◽  
Human Brain Tissue

ObjectiveMyotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old.MethodsWe used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data.ResultsAge was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10.ConclusionsPeak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.

Cell Type–Specific Nuclei Markers: The Need for Human Brain Research to Go Nuclear

2021 ◽  
pp. 107385842110373
Author(s):  
James A. Wiseman ◽  
Mike Dragunow ◽  
Thomas I.-H. Park
Keyword(s):  
Human Brain ◽  
Brain Research ◽  
Cell Types ◽  
Brain Cell ◽  
Normal Brain ◽  
Cell Type ◽  
Human Brain Tissue ◽  
Nuclear Markers ◽  
Cell Type Specific ◽  
Immunohistochemical Studies

Identifying and interrogating cell type–specific populations within the heterogeneous milieu of the human brain is paramount to resolving the processes of normal brain homeostasis and the pathogenesis of neurological disorders. While brain cell type–specific markers are well established, most are localized on cellular membranes or within the cytoplasm, with limited literature describing those found in the nucleus. Due to the complex cytoarchitecture of the human brain, immunohistochemical studies require well-defined cell-specific nuclear markers for more precise and efficient quantification of the cellular populations. Furthermore, efficient nuclear markers are required for cell type–specific purification and transcriptomic interrogation of archived human brain tissue through nuclei isolation–based RNA sequencing. To sate the growing demand for robust cell type–specific nuclear markers, we thought it prudent to comprehensively review the current literature to identify and consolidate a novel series of robust cell type–specific nuclear markers that can assist researchers across a range of neuroscientific disciplines. The following review article collates and discusses several key and prospective cell type–specific nuclei markers for each of the major human brain cell types; it then concludes by discussing the potential applications of cell type–specific nuclear workflows and the power of nuclear-based neuroscientific research.

scholarly journals Trace elements during primordial plexiform network formation in human cerebral organoids

2016 ◽  
Author(s):  
Rafaela C Sartore ◽  
Simone C Cardoso ◽  
Yuri V Lages ◽  
Julia M Paraguassu ◽  
Rodrigo F Madeiro da Costa ◽  
...  
Keyword(s):  
Trace Elements ◽  
Human Brain ◽  
Pluripotent Stem Cells ◽  
Cell Biology ◽  
Network Formation ◽  
Biological Processes ◽  
Human Brain Tissue ◽  
Human Brain Development ◽  
Calcium Iron ◽  
Human Telencephalon

Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon development. In the present work, we exposed cerebral organoids derived from human pluripotent stem cells to synchrotron radiation in order to measure how biologically valuable micronutrients are incorporated and distributed in the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves calcium, iron, phosphorus, potassium, sulfur, and zinc. Local trends in concentrations suggest a switch from passive to actively mediated transport across cell membranes. Finally, correlational analysis for pairs of elements shows spatially conserved patterns, suggesting they may physically associate, be stored in similar compartments or used in related biological processes. These findings might reflect which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood.

scholarly journals Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Juan Luo ◽  
Peng Li
Keyword(s):  
Human Brain ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Resource Limitation ◽  
In Vitro Models ◽  
Human Brain Tissue ◽  
Self Organized ◽  
Future Direction ◽  
Neural Disorders

AbstractThe sheer complexities of brain and resource limitation of human brain tissue greatly hamper our understanding of the brain disorders and cancers. Recently developed three-dimensional (3D) brain organoids (BOs) are self-organized and spontaneously differentiated from human pluripotent stem cells (hPSCs) in vitro, which exhibit similar features with cell type diversity, structural organization, and functional connectivity as the developing human brain. Based on these characteristics, hPSC-derived BOs (hPDBOs) provide new opportunities to recapitulate the complicated processes during brain development, neurodegenerative disorders, and brain cancers in vitro. In this review, we will provide an overview of existing BO models and summarize the applications of this technology in modeling the neural disorders and cancers. Furthermore, we will discuss the challenges associated with their use as in vitro models for disease modeling and the potential future direction.

A Life Span Developmental Approach

2005 ◽  
Author(s):  
James C. Harris
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
Life Span ◽  
Cognitive Processing ◽  
Network Formation ◽  
Developmental Trajectories ◽  
Neurodevelopmental Disorder ◽  
Normal Brain ◽  
The Brain ◽  
Normal Brain Development

Intellectual disability is a neurodevelopmental disorder that continues throughout the life span of the affected person. It is essential to understand how persons with intellectual disability progress throughout their life span from infancy to old age. The maturation of the brain, their environmental experiences, and the mastery of developmental challenges and tasks must all be considered. A focus on brain development is in keeping with neuroscience research indicating that progressive brain maturation is accompanied by successive synaptic reorganization as one moves from one developmental stage to the next. Anatomical Magnetic Resonance Imaging Studies are playing a major role in understanding the developmental trajectories of normal brain development (Durston et al., 2001; Giedd et al., 1999). Understanding the developmental trajectories of normal brain development is crucial to the interpretation of brain development in neurodevelopmental disabilities. During normal development, white matter volume increases with age, and although gray matter volumes increase during childhood, they decrease before adulthood. These changes in the brain are accompanied by changes in cognitive processing; for example, executive functioning shows a progressive emergence from the preschool years (Espy et al., 1999) into the adolescent years. Working memory and inhibitory processes may be measured during the preschool years. By adolescence, abstract reasoning, anticipatory planning, and mental judgment have emerged and may be measured. Cognitive abilities in adolescence are qualitatively different from those of young children as a result of the reorganization of the prefrontal cortex during maturation. How genetic background and environment interact in producing these changes is the object of ongoing study, yet investigators are beginning to understand how physiological processes of synaptic development, circuits, and neuronal network formation relate to processes of cognitive development (Fossella et al., 2003). The development of persons with intellectual disability is now being evaluated systematically, and developmental trajectories are being established for known neurogenetic syndromes. These studies are making up for a surprising lack of application of a developmental perspective to persons with intellectual disability. Developmental theorists have, for the most part, monitored and measured development in normally intelligent persons in establishing developmental landmarks.

scholarly journals Trace elements during primordial plexiform network formation in human cerebral organoids

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2927 ◽  
Author(s):  
Rafaela C. Sartore ◽  
Simone C. Cardoso ◽  
Yury V.M. Lages ◽  
Julia M. Paraguassu ◽  
Mariana P. Stelling ◽  
...  
Keyword(s):  
Trace Elements ◽  
Human Brain ◽  
Cell Biology ◽  
Network Formation ◽  
Interaction Patterns ◽  
Human Brain Tissue ◽  
Concentration Gradients ◽  
Human Telencephalon

Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon developmentin vitro. In the present work, we analyzed cerebral organoids derived from human pluripotent stem cells by synchrotron radiation X-ray fluorescence in order to measure biologically valuable micronutrients incorporated and distributed into the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves P, S, K, Ca, Fe and Zn. Occurrence of different concentration gradients also suggests active regulation of elemental transmembrane transport. Finally, the analysis of pairs of elements shows interesting elemental interaction patterns that change from 30 to 45 days of development, suggesting short- or long-term associations, such as storage in similar compartments or relevance for time-dependent biological processes. These findings shed light on which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood.

scholarly journals Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971

2021 ◽  
Author(s):  
Nisha K. Ramakrishnan ◽  
Matthew Hird ◽  
Stephen Thompson ◽  
David J. Williamson ◽  
Luxi Qiao ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Rhesus Macaques ◽  
Biological Evaluation ◽  
Translocator Protein ◽  
Normal Brain ◽  
Human Brain Tissue ◽  
Peripheral Tissues ◽  
Low Sensitivity ◽  
The Brain

Abstract Purpose Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism. Methods Dynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue. Results (S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8. Conclusion We established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.

Sign in / Sign up

Export Citation Format

Share Document