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Engineering regional diversity: A morphogen screen for patterned brain organoids.
Morphogens orchestrate cellular diversity during nervous system development, yet a systematic approach to harnessing these signals in stem cell differentiation remains elusive. Amin et al.1 present a platform integrating parallel morphogen modulator screening with single-cell sequencing of neural organoids, reinforcing brain regionalization principles and enabling detailed cellular annotation.
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Brain Organoids as Tools for Modeling Human Neurodevelopmental Disorders.
Brain organoids recapitulate in vitro the specific stages of in vivo human brain development, thus offering an innovative tool by which to model human neurodevelopmental disease. We review here how brain organoids have been used to study neurodevelopmental disease and consider their potential for both technological advancement and therapeutic development.
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Opportunities and challenges of glioma organoids.
Glioma is the most common primary brain tumor and its prognosis is poor. Despite surgical removal, glioma is still prone to recurrence because it grows rapidly in the brain, is resistant to chemotherapy, and is highly aggressive. Therefore, there is an urgent need for a platform to study the cell dynamics of gliomas in order to discover the characteristics of the disease and develop more effective treatments. Although 2D cell models and animal models in previous studies have provided great help for our research, they also have many defects. Recently, scientific researchers have constructed a 3D structure called Organoids, which is similar to the structure of human tissues and organs. Organoids can perfectly compensate for the shortcomings of previous glioma models and are currently the most suitable research platform for glioma research. Therefore, we review the three methods currently used to establish glioma organoids. And introduced how they play a role in the diagnosis and treatment of glioma. Finally, we also summarized the current bottlenecks and difficulties encountered by glioma organoids, and the current efforts to solve these difficulties. Video Abstract.
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Vascularized human brain organoids: current possibilities and prospects.
Human brain organoids (hBOs) are in vitro, 3D, self-organizing brain tissue structures increasingly used for modeling brain development and disease. Although they traditionally lack vasculature, recent bioengineering developments enable their vascularization, which partly recapitulates neurodevelopmental processes such as neural tube angiogenesis, formation of neurovascular unit (NVU)-like structures, and early barriergenesis. Although vascularized hBOs (vhBOs) are already used to model (defects in) neurovascular development, vascularization efficiency and other outcomes differ substantially between vascularization protocols and overall shortcomings should be considered. For instance, vessel-like structures in vhBOs do not contain blood-like flow nor do they form a functional blood-brain barrier (BBB). Extended characterization, standardization, and the development of new bioengineering techniques may enable broader applications of vhBOs such as drug transport studies.
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Modelling neurodegenerative disease using brain organoids.
Neurodegenerative Diseases such as Alzheimer's Disease represent a major public health challenge, with no disease modifying therapies available. The availability of induced pluripotent stem cells from patients with phenotypes and genotypes of interest, that can be subsequently differentiated in vitro into disease-affected cell types, has revolutionised our ability to generate physiologically relevant disease models. The recent availability of brain organoids - self-organising in vitro tissue models - as enabled the generation of complex, multicellular systems to study brain development and disease. Although widely used for modelling neurodevelopment, early studies have demonstrated great promise in the use of organoids as models of neurodegenerative disease. Here, I will review recent progress to model neurodegenerative diseases using organoids and comment on future directions and challenges.
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New Pioneers of Optogenetics in Neuroscience.
Optogenetics have recently increased in popularity as tools to study behavior in response to the brain and how these trends relate back to a neuronal circuit. Additionally, the high demand for human cerebral tissue in research has led to the generation of a new model to investigate human brain development and disease. Human Pluripotent Stem Cells (hPSCs) have been previously used to recapitulate the development of several tissues such as intestine, stomach and liver and to model disease in a human context, recently new improvements have been made in the field of hPSC-derived brain organoids to better understand overall brain development but more specifically, to mimic inter-neuronal communication. This review aims to highlight the recent advances in these two separate approaches of brain research and to emphasize the need for overlap. These two novel approaches would combine the study of behavior along with the specific circuits required to produce the signals causing such behavior. This review is focused on the current state of the field, as well as the development of novel optogenetic technologies and their potential for current scientific study and potential therapeutic use.
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Using organoids to study human brain development and evolution.
Recent advances in methods for making cerebral organoids have opened a window of opportunity to directly study human brain development and disease, countering limitations inherent in non-human-based approaches. Whether freely patterned, guided into a region-specific fate or fused into assembloids, organoids have successfully recapitulated key features of in vivo neurodevelopment, allowing its examination from early to late stages. Although organoids have enormous potential, their effective use relies on understanding the extent of their limitations in accurately reproducing specific processes and components in the developing human brain. Here we review the potential of cerebral organoids to model and study human brain development and evolution and discuss the progress and current challenges in their use for reproducing specific human neurodevelopmental processes.
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Androgens increase excitatory neurogenic potential in human brain organoids.
The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals1,2, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids3 to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.
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Generation of mouse hippocampal brain organoids from primary embryonic neural stem cells.
Here we present a protocol to generate standardized cerebral organoids with hippocampal regional specification using morphogen WNT3a. We describe steps for isolating mouse embryonic (E14.5) neural stem cells from the brain subgranular zone, preparing organoids samples for immunofluorescence, calcium imaging, and metabolic profiling. This protocol can be used to generate mouse brain organoids for developmental studies, modeling disease, and drug screening. Organoids can be obtained in one month, thus providing a rapid tool for high-throughput data validation. For complete details on the use and execution of this protocol, please refer to Ciarpella et al. "Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity".1.
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The ethics of experimenting with human brain tissue.