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1
Yu, Xiyao, Xiaoting Meng, Zhe Pei, Guoqiang Wang, Rongrong Liu, Mingran Qi, Jiaying Zhou, and Fang Wang. "Physiological Electric Field: A Potential Construction Regulator of Human Brain Organoids." International Journal of Molecular Sciences 23, no. 7 (March 31, 2022): 3877. http://dx.doi.org/10.3390/ijms23073877.
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Brain organoids can reproduce the regional three-dimensional (3D) tissue structure of human brains, following the in vivo developmental trajectory at the cellular level; therefore, they are considered to present one of the best brain simulation model systems. By briefly summarizing the latest research concerning brain organoid construction methods, the basic principles, and challenges, this review intends to identify the potential role of the physiological electric field (EF) in the construction of brain organoids because of its important regulatory function in neurogenesis. EFs could initiate neural tissue formation, inducing the neuronal differentiation of NSCs, both of which capabilities make it an important element of the in vitro construction of brain organoids. More importantly, by adjusting the stimulation protocol and special/temporal distributions of EFs, neural organoids might be created following a predesigned 3D framework, particularly a specific neural network, because this promotes the orderly growth of neural processes, coordinate neuronal migration and maturation, and stimulate synapse and myelin sheath formation. Thus, the application of EF for constructing brain organoids in a3D matrix could be a promising future direction in neural tissue engineering.
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Pflug, Florian G., Simon Haendeler, Christopher Esk, Dominik Lindenhofer, Jürgen A. Knoblich, and Arndt von Haeseler. "Neutral competition explains the clonal composition of neural organoids." PLOS Computational Biology 20, no. 4 (April 22, 2024): e1012054. http://dx.doi.org/10.1371/journal.pcbi.1012054.
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Neural organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progenies arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This high variability exceeds what can be explained by existing stochastic models of corticogenesis and indicates the existence of an additional source of stochasticity. To explain this variability, we introduce the SAN model which distinguishes Symmetrically diving, Asymmetrically dividing, and Non-proliferating cells. In the SAN model, the additional source of stochasticity is the survival time of a lineage’s pool of symmetrically dividing cells. These survival times result from neutral competition within the sub-population of all symmetrically dividing cells. We demonstrate that our model explains the experimentally observed variability of lineage sizes and derive the quantitative relationship between survival time and lineage size. We also show that our model implies the existence of a regulatory mechanism which keeps the size of the symmetrically dividing cell population constant. Our results provide quantitative insight into the clonal composition of neural organoids and how it arises. This is relevant for many applications of neural organoids, and similar processes may occur in other developing tissues both in vitro and in vivo.
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Logan, Sarah, Thiago Arzua, Yasheng Yan, Congshan Jiang, Xiaojie Liu, Lai-Kang Yu, Qing-Song Liu, and Xiaowen Bai. "Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles." Cells 9, no. 5 (May 23, 2020): 1301. http://dx.doi.org/10.3390/cells9051301.
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Background: The development of 3D cerebral organoid technology using human-induced pluripotent stem cells (iPSCs) provides a promising platform to study how brain diseases are appropriately modeled and treated. So far, understanding of the characteristics of organoids is still in its infancy. The current study profiled, for the first time, the electrophysiological properties of organoids at molecular and cellular levels and dissected the potential age equivalency of 2-month-old organoids to human ones by a comparison of gene expression profiles among cerebral organoids, human fetal and adult brains. Results: Cerebral organoids exhibit heterogeneous gene and protein markers of various brain cells, such as neurons, astrocytes, and vascular cells (endothelial cells and smooth muscle cells) at 2 months, and increases in neural, glial, vascular, and channel-related gene expression over a 2-month differentiation course. Two-month organoids exhibited action potentials, multiple channel activities, and functional electrophysiological responses to the anesthetic agent propofol. A bioinformatics analysis of 20,723 gene expression profiles showed the similar distance of gene profiles in cerebral organoids to fetal and adult brain tissues. The subsequent Ingenuity Pathway Analysis (IPA) of select canonical pathways related to neural development, network formation, and electrophysiological signaling, revealed that only calcium signaling, cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling in neurons, glutamate receptor signaling, and synaptogenesis signaling were predicted to be downregulated in cerebral organoids relative to fetal samples. Nearly all cerebral organoid and fetal pathway phenotypes were predicted to be downregulated compared with adult tissue. Conclusions: This novel study highlights dynamic development, cellular heterogeneity and electrophysiological activity. In particular, for the first time, electrophysiological drug response recapitulates what occurs in vivo, and neural characteristics are predicted to be highly similar to the human brain, further supporting the promising application of the cerebral organoid system for the modeling of the human brain in health and disease. Additionally, the studies from these characterizations of cerebral organoids in multiple levels and the findings from gene comparisons between cerebral organoids and humans (fetuses and adults) help us better understand this cerebral organoid-based cutting-edge platform and its wide uses in modeling human brain in terms of health and disease, development, and testing drug efficacy and toxicity.
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Kim, Soo-hyun, and Mi-Yoon Chang. "Application of Human Brain Organoids—Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases." International Journal of Molecular Sciences 24, no. 15 (August 7, 2023): 12528. http://dx.doi.org/10.3390/ijms241512528.
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Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that reflect early brain organization. These organoids contain different cell types, including neurons and glia, similar to those found in the human brain. Human brain organoids provide unique opportunities to model features of human brain development that are not well-reflected in animal models. Compared with traditional cell cultures and animal models, brain organoids offer a more accurate representation of human brain development and function, rendering them suitable models for neurodevelopmental diseases. In particular, brain organoids derived from patients’ cells have enabled researchers to study diseases at different stages and gain a better understanding of disease mechanisms. Multi-brain regional assembloids allow for the investigation of interactions between distinct brain regions while achieving a higher level of consistency in molecular and functional characterization. Although organoids possess promising features, their usefulness is limited by several unresolved constraints, including cellular stress, hypoxia, necrosis, a lack of high-fidelity cell types, limited maturation, and circuit formation. In this review, we discuss studies to overcome the natural limitations of brain organoids, emphasizing the importance of combinations of all neural cell types, such as glia (astrocyte, oligodendrocytes, and microglia) and vascular cells. Additionally, considering the similarity of organoids to the developing brain, regionally patterned brain organoid-derived neural stem cells (NSCs) could serve as a scalable source for cell replacement therapy. We highlight the potential application of brain organoid-derived cells in disease cell therapy within this field.
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Mensah-Brown, Kobina G., James Lim, Dennis Jgamadze, Guo-li Ming, Hongjun Song, John A. Wolf, and Han-Chiao I. Chen. "96101 Temporal Evolution of Neural Activity in Human Brain Organoids." Journal of Clinical and Translational Science 5, s1 (March 2021): 23. http://dx.doi.org/10.1017/cts.2021.464.
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ABSTRACT IMPACT: This study will provide the essential characterization of intrinsic neural activity in human brain organoids, both at the single cell and network levels, to harness for translational purposes. OBJECTIVES/GOALS: Brain organoids are 3D, stem cell-derived neural tissues that recapitulate neurodevelopment. However, to levy their full translational potential, a deeper understanding of their intrinsic neural activity is essential. Here, we present our preliminary analysis of maturing neural activity in human forebrain organoids. METHODS/STUDY POPULATION: Forebrain organoids were generated from human iPSC lines derived from healthy volunteers. Linear microelectrode probes were employed to record spontaneous electrical activity from day 77, 100, and 130 organoids. Single unit recordings were collected during hour-long recordings, involving baseline recordings followed by glutamatergic blockade. Subsequently, tetrodotoxin, was used to abolish action potential firing. Single units were identified via spike sorting, and the spatiotemporal evolution of baseline neural properties and network dynamics was characterized. RESULTS/ANTICIPATED RESULTS: Nine organoids were recorded successfully (n=3 per timepoint). A significant difference in number of units was seen across age groups (F (2,6) = 6.4178, p = 0.0323). Post hoc comparisons by the Tukey HSD test showed significantly more units in day 130 (51.67 ±14.15) than day 77 (16.33 ±14.98) organoids. Mean firing rates were significantly different in organoids based on age, with drug condition also trending toward significance (F (6,12) = 9.97; p = 0.0028 and p = 0.08 respectively). Post hoc comparisons showed a higher baseline firing rate in day 130 (0.99Hz ±0.30) organoids than their day 77 counterparts at baseline (0.31Hz ±0.066) and glutamate blockade (0.31Hz ±0.045). Preliminary network analysis showed no modularity or small-world features; however, these features are expected to emerge as organoids mature. DISCUSSION/SIGNIFICANCE OF FINDINGS: Initial analysis of brain organoid activity demonstrates changes in single unit properties as they mature. Additional work in this area, as well as further network analyses, will confer better sense of how to rationally utilize brain organoids for translational purposes.
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Birch, Jonathan. "When is a brain organoid a sentience candidate?" Molecular Psychology: Brain, Behavior, and Society 2 (October 18, 2023): 22. http://dx.doi.org/10.12688/molpsychol.17524.1.
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It would be unwise to dismiss the possibility of human brain organoids developing sentience. However, scepticism about this idea is appropriate when considering current organoids. It is a point of consensus that a brainstem-dead human is not sentient, and current organoids lack a functioning brainstem. There are nonetheless troubling early warning signs, suggesting organoid research may create forms of sentience in the near future. To err on the side of caution, researchers with very different views about the neural basis of sentience should unite behind the “brainstem rule”: if a neural organoid develops or innervates a functioning brainstem that registers and prioritizes its needs, regulates arousal, and leads to sleep-wake cycles, then it is a sentience candidate. If organoid research leads to the creation of sentience candidates, a moratorium or indefinite ban on the creation of the relevant type of organoid may be appropriate. A different way forward, more consistent with existing approaches to animal research, would be to require ethical review and harm-benefit analysis for all research on sentience candidates.
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Tanaka, Yoshiaki, and In-Hyun Park. "Regional specification and complementation with non-neuroectodermal cells in human brain organoids." Journal of Molecular Medicine 99, no. 4 (March 2, 2021): 489–500. http://dx.doi.org/10.1007/s00109-021-02051-9.
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AbstractAlong with emergence of the organoids, their application in biomedical research has been currently one of the most fascinating themes. For the past few years, scientists have made significant contributions to deriving organoids representing the whole brain and specific brain regions. Coupled with somatic cell reprogramming and CRISPR/Cas9 editing, the organoid technologies were applied for disease modeling and drug screening. The methods to develop organoids further improved for rapid and efficient generation of cerebral organoids. Additionally, refining the methods to develop the regionally specified brain organoids enabled the investigation of development and interaction of the specific brain regions. Recent studies started resolving the issue in the lack of non-neuroectodermal cells in brain organoids, including vascular endothelial cells and microglia, which play fundamental roles in neurodevelopment and are involved in the pathophysiology of acute and chronic neural disorders. In this review, we highlight recent advances of neuronal organoid technologies, focusing on the region-specific brain organoids and complementation with endothelial cells and microglia, and discuss their potential applications to neuronal diseases.
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Katayama, Masafumi, Manabu Onuma, Noriko Kato, Nobuyoshi Nakajima, and Tomokazu Fukuda. "Organoids containing neural-like cells derived from chicken iPSCs respond to poly:IC through the RLR family." PLOS ONE 18, no. 5 (May 4, 2023): e0285356. http://dx.doi.org/10.1371/journal.pone.0285356.
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There is still much room for development in pluripotent stem cell research on avian species compared to human stem cell studies. Neural cells are useful for the evaluation of risk assessment of infectious diseases since several avian species die of encephalitis derived from infectious diseases. In this study, we attempted to develop induced pluripotent stem cells (iPSCs) technology for avian species by forming organoids containing neural-like cells. In our previous study, we established two types iPSCs from chicken somatic cells, the first is iPSCs with PB-R6F reprogramming vector and the second is iPSCs with PB-TAD-7F reprogramming vector. In this study, we first compared the nature of these two cell types using RNA-seq analysis. The total gene expression of iPSCs with PB-TAD-7F was closer to that of chicken ESCs than that of iPSCs with PB-R6F; therefore, we used iPSCs with PB-TAD-7F to form organoids containing neural-like cells. We successfully established organoids containing neural-like cells from iPSCs using PB-TAD-7F. Furthermore, our organoids responded to poly:IC through the RIG-I-like receptor (RLR) family. In this study, we developed iPSCs technology for avian species via organoid formation. In the future, organoids containing neural-like cells from avian iPSCs can develop as a new evaluation tool for infectious disease risk in avian species, including endangered avian species.
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Zhou, Gang, Siyuan Pang, Yongning Li, and Jun Gao. "Progress in the generation of spinal cord organoids over the past decade and future perspectives." Neural Regeneration Research 19, no. 5 (September 22, 2023): 1013–19. http://dx.doi.org/10.4103/1673-5374.385280.
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Abstract Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo. As emerging bioengineering methods have led to the optimization of cell culture protocols, spinal cord organoids technology has made remarkable advancements in the past decade. Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes. Moreover, fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment. These qualities make spinal cord organoids valuable tools for disease modeling, drug screening, and tissue regeneration. By utilizing this emergent technology, researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases. However, at present, spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine. Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.
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Luo, Kevin. "Application of neural organoids in studying neurodegenerative diseases." Theoretical and Natural Science 15, no. 1 (December 4, 2023): 166–70. http://dx.doi.org/10.54254/2753-8818/15/20240474.
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Neurodegenerative diseases are among the top causes of mortality and the aversion of DALYs (Disability-Adjusted Life Years) worldwide. Many attempts have been made to develop therapeutics to alleviate disease symptoms without much success. The preclinical models utilized in therapeutic testing are often inaccurate and cannot precisely translate into clinical studies. The introduction of neural organoids, a three-dimensional model grown from human-originated stem cells, was able to revolutionize the field of neurological drug development. Using induced pluripotent stem cell (iPSC), scientists are able to restore adult cells pluripotency and cultivate them into region specific brain organoids using a combination of growth factors, agonists, and inhibitors. These models have proven valuable in drug screen for myriad neurodegenerative disorders. To model such diseases, iPSCs are generated from patients with the respective diseases, and then cultivated in an environment that mimics the disease environment. For example, for Parkinsons disease, Wnt pathway inhibitors and the Sonic hedgehog agonist are used to induce midbrain neural progenitor cells from patients with risk factors. Despite neural organoids wide usage in screening for neurodegenerative disorders and drug testing, neural organoids present several limitations in their function, including a lack of complexity equivalent to that of the brain. This paper will discuss neural organoid technology and provide basic insight to its usage in drug screening and the field of neuroscience.
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Kiaee, Kiavash, Yasamin A. Jodat, Nicole J. Bassous, Navneet Matharu, and Su Ryon Shin. "Transcriptomic Mapping of Neural Diversity, Differentiation and Functional Trajectory in iPSC-Derived 3D Brain Organoid Models." Cells 10, no. 12 (December 5, 2021): 3422. http://dx.doi.org/10.3390/cells10123422.
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Experimental models of the central nervous system (CNS) are imperative for developmental and pathophysiological studies of neurological diseases. Among these models, three-dimensional (3D) induced pluripotent stem cell (iPSC)-derived brain organoid models have been successful in mitigating some of the drawbacks of 2D models; however, they are plagued by high organoid-to-organoid variability, making it difficult to compare specific gene regulatory pathways across 3D organoids with those of the native brain. Single-cell RNA sequencing (scRNA-seq) transcriptome datasets have recently emerged as powerful tools to perform integrative analyses and compare variability across organoids. However, transcriptome studies focusing on late-stage neural functionality development have been underexplored. Here, we combine and analyze 8 brain organoid transcriptome databases to study the correlation between differentiation protocols and their resulting cellular functionality across various 3D organoid and exogenous brain models. We utilize dimensionality reduction methods including principal component analysis (PCA) and uniform manifold approximation projection (UMAP) to identify and visualize cellular diversity among 3D models and subsequently use gene set enrichment analysis (GSEA) and developmental trajectory inference to quantify neuronal behaviors such as axon guidance, synapse transmission and action potential. We showed high similarity in cellular composition, cellular differentiation pathways and expression of functional genes in human brain organoids during induction and differentiation phases, i.e., up to 3 months in culture. However, during the maturation phase, i.e., 6-month timepoint, we observed significant developmental deficits and depletion of neuronal and astrocytes functional genes as indicated by our GSEA results. Our results caution against use of organoids to model pathophysiology and drug response at this advanced time point and provide insights to tune in vitro iPSC differentiation protocols to achieve desired neuronal functionality and improve current protocols.
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Sureshkumar, Akash, Shilpa Bisht, and Hariharan Easwaran. "Abstract 230: Deep learning embedding-based segmentation for morphological analysis in organoids." Cancer Research 84, no. 6_Supplement (March 22, 2024): 230. http://dx.doi.org/10.1158/1538-7445.am2024-230.
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Abstract Background: The organoid model is a useful tool for modeling the cellular microenvironment of the organ from which they are derived. Organoids recapitulate the self-organization of heterogenous cell types and the microenvironment. Quantifying the morphological features of organoids can provide valuable insights into cellular organizational defects and growth characteristics, which can facilitate drug discovery. Measurement of these characteristics in live organoids can be performed quickly and easily directly in culture using widefield microscopy. The current state-of-the-art method to detect and identify the shape of individual organoids in brightfield images uses the U-Net Convolutional Neural Network (CNN) with a watershed transform to label pixels. However, this method yields jagged shape proposals and cannot detect overlapping regions. We propose the use of an embedding-based segmentation network based on the Branched ERF-Net to solve these issues. Methods: Organoids were established from the proximal colon of BrafV600E heterozygous mice, and 50 phase-contrast images of the organoids were acquired at 2.5x and 4x magnification. Organoids present in acquired images were labeled manually. The network was trained on this collection of manually labeled images and validated on a separate validation dataset. Results: The network accurately labels organoids. Overlapping organoids are segmented correctly and shape proposals are smoother. Detection of overlapping organoids with the Branched ERF-Net architecture yields an accurate organoid count, verified against manual counting. Smoother shape proposals also enable the use of convexity defects to measure organoid budding. Conclusions: Deep-learning analysis of widefield images enables the rapid assessment of morphological characteristics, such as size, count, and budding, which are key to understanding proliferation and differentiation changes. The modified Branched ERF-Net architecture we propose for organoid segmentation is a robust and versatile method to quantify organoid morphology. Citation Format: Akash Sureshkumar, Shilpa Bisht, Hariharan Easwaran. Deep learning embedding-based segmentation for morphological analysis in organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 230.
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Bao, Zhongyuan, Kaiheng Fang, Zong Miao, Chong Li, Chaojuan Yang, Qiang Yu, Chen Zhang, Zengli Miao, Yan Liu, and Jing Ji. "Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice." Oxidative Medicine and Cellular Longevity 2021 (November 22, 2021): 1–16. http://dx.doi.org/10.1155/2021/6338722.
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Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell- (hESC-) derived cerebral organoids in the brain lesions of controlled cortical impact- (CCI-) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI-induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice’s spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.
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Camp, J. Gray, Farhath Badsha, Marta Florio, Sabina Kanton, Tobias Gerber, Michaela Wilsch-Bräuninger, Eric Lewitus, et al. "Human cerebral organoids recapitulate gene expression programs of fetal neocortex development." Proceedings of the National Academy of Sciences 112, no. 51 (December 7, 2015): 15672–77. http://dx.doi.org/10.1073/pnas.1520760112.
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Cerebral organoids—3D cultures of human cerebral tissue derived from pluripotent stem cells—have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.
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Harary, Paul M., Rachel Blue, Mackenzie Castellanos, Mehek Dedhia, Sarah Hamimi, Dennis Jgamadze, Benjamin Rees, et al. "Human brain organoid transplantation: ethical implications of enhancing specific cerebral functions in small-animal models." Molecular Psychology: Brain, Behavior, and Society 2 (June 6, 2023): 14. http://dx.doi.org/10.12688/molpsychol.17544.1.
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Brain organoids are self-organizing, three-dimensional tissues derived from pluripotent stem cells that recapitulate many aspects of the cellular diversity and architectural features of the developing brain. Recently, there has been growing interest in using human brain organoid transplantation in animal models as a means of addressing the limitations of in vitro culture, such as the lack of vascularization, and to explore the potential of organoids for neural repair. While there has been substantial debate on the ethical implications of brain organoid research, particularly the potential for organoids to exhibit higher-order brain functions such as consciousness, the impact of human organoid grafts on animal hosts has been less extensively discussed. Enhancement of host animal brain function may not be technically feasible at this time, but it is imperative to carefully consider the moral significance of these potential outcomes. Here, we discuss the ethical implications of enhancing somatosensation, motor processes, memory, and basic socialization in small-animal models. We consider the moral implications of such outcomes and if safeguards are needed to accommodate any increased moral status of animals transplanted with human brain organoids.
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da Silva, Bárbara, Ryan K. Mathew, Euan S. Polson, Jennifer Williams, and Heiko Wurdak. "Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 8 (March 15, 2018): 862–68. http://dx.doi.org/10.1177/2472555218764623.
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Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from noncancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modeling and quantification of the GBM infiltration process using a stem-cell-based organoid approach, and may be used for the identification of anti-GBM invasion strategies.
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Hopkins, Hannah K., Elizabeth M. Traverse, and Kelli L. Barr. "Methodologies for Generating Brain Organoids to Model Viral Pathogenesis in the CNS." Pathogens 10, no. 11 (November 19, 2021): 1510. http://dx.doi.org/10.3390/pathogens10111510.
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(1) Background: The human brain is of interest in viral research because it is often the target of viruses. Neurological infections can result in consequences in the CNS, which can result in death or lifelong sequelae. Organoids modeling the CNS are notable because they are derived from stem cells that differentiate into specific brain cells such as neural progenitors, neurons, astrocytes, and glial cells. Numerous protocols have been developed for the generation of CNS organoids, and our goal was to describe the various CNS organoid models available for viral pathogenesis research to serve as a guide to determine which protocol might be appropriate based on research goal, timeframe, and budget. (2) Methods: Articles for this review were found in Pubmed, Scopus and EMBASE. The search terms used were “brain + organoid” and “CNS + organoid” (3) Results: There are two main methods for organoid generation, and the length of time for organoid generation varied from 28 days to over 2 months. The costs for generating a population of organoids ranged from USD 1000 to 5000. (4) Conclusions: There are numerous methods for generating organoids representing multiple regions of the brain, with several types of modifications for fine-tuning the model to a researcher’s specifications. Organoid models of the CNS can serve as a platform for characterization and mechanistic studies that can reduce or eliminate the use of animals, especially for viruses that only cause disease in the human CNS.
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Kim, Min Soo, Da-Hyun Kim, Hyun Kyoung Kang, Myung Geun Kook, Soon Won Choi, and Kyung-Sun Kang. "Modeling of Hypoxic Brain Injury through 3D Human Neural Organoids." Cells 10, no. 2 (January 25, 2021): 234. http://dx.doi.org/10.3390/cells10020234.
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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.
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Mukashyaka, Patience, Pooja Kumar, Dave Mellert, Shadae Nicholas, Javad Noorbakhsh, Mattia Brugiolo, Olga Anczukow, Edison T. Liu, and Jeffrey H. Chuang. "Abstract 186: Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology." Cancer Research 83, no. 7_Supplement (April 4, 2023): 186. http://dx.doi.org/10.1158/1538-7445.am2023-186.
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Abstract Three-dimensional (3D) culture models, such as organoids, are flexible systems to interrogate cellular growth, multicellular spatial architecture, and morphology in response to drug treatment, including the potential to resolve the individual behaviors and interactions of mixed cancer cell populations. However, new computational methods to segment and analyze 3D models at cellular resolution are needed to realize these possibilities. Here we report Cellos (Cell Organoid Segmentation), an accurate, high throughput image analysis pipeline for 3D organoid and nuclear segmentation analysis. Cellos segments 3D organoids using classical algorithms and segments nuclei using a Stardist-3D convolutional neural network trained on a manually annotated dataset of 3,862 cells from 36 organoids confocally imaged at 5 μm z-resolution. To evaluate the capabilities of Cellos, we then analyzed 74,450 organoids with 1.65 million cells from multiple experiments on triple negative breast cancer organoids containing clonal mixtures with complex cisplatin sensitivity. Cellos was able to accurately distinguish cell ratios in organoids in 96-well plates to within 2.99% and was effective for fluorescently labelled nuclei and independent DAPI stained datasets. Cellos was able to recapitulate traditional luminescence based drug responses by analyzing 3D images, including parallel analysis of multiple cancer clones in the same well. Moreover, Cellos was able to identify organoid and nuclear morphology feature changes associated with treatment. Finally, Cellos enables 3D analysis of cell spatial relationships, which we used to detect ecological affinity between cancer cells, beyond expectations from local cell division or organoid composition. Cellos provides powerful tools to perform high throughput analysis for pharmacological testing and biological investigation of organoids based on 3D imaging. Citation Format: Patience Mukashyaka, Pooja Kumar, Dave Mellert, Shadae Nicholas, Javad Noorbakhsh, Mattia Brugiolo, Olga Anczukow, Edison T. Liu, Jeffrey H. Chuang. Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 186.
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Wu, Yihui, Jin Qiu, Shuilian Chen, Xi Chen, Jing Zhang, Jiejie Zhuang, Sian Liu, et al. "Comparison of the Response to the CXCR4 Antagonist AMD3100 during the Development of Retinal Organoids Derived from ES Cells and Zebrafish Retina." International Journal of Molecular Sciences 23, no. 13 (June 25, 2022): 7088. http://dx.doi.org/10.3390/ijms23137088.
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Retinal organoids generated from human embryonic stem cells or iPSCs recreate the key structural and functional features of mammalian retinal tissue in vitro. However, the differences in the development of retinal organoids and normal retina in vivo are not well defined. Thus, in the present study, we analyzed the development of retinal organoids and zebrafish retina after inhibition of CXCR4, a key role in neurogenesis and optic nerve development, with the antagonist AMD3100. Our data indicated that CXCR4 was mainly expressed in ganglion cells in retinal organoids and was rarely expressed in amacrine or photoreceptor cells. AMD3100 treatment reduced the retinal organoid generation ratio, impaired differentiation, and induced morphological changes. Ganglion cells, amacrine cells, and photoreceptors were decreased and abnormal locations were observed in organoids treated with AMD3100. Neuronal axon outgrowth was also damaged in retinal organoids. Similarly, a decrease of ganglion cells, amacrine cells, and photoreceptors and the distribution of neural outgrowth was induced by AMD3100 treatment in zebrafish retina. However, abnormal photoreceptor ensembles induced by AMD3100 treatment in the organoids were not detected in zebrafish retina. Therefore, our study suggests that although retinal organoids might provide a reliable model for reproducing a retinal developmental model, there is a difference between the organoids and the retina in vivo.
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Sapir, Gal, Daniel J. Steinberg, Rami I. Aqeilan, and Rachel Katz-Brull. "Real-Time Non-Invasive and Direct Determination of Lactate Dehydrogenase Activity in Cerebral Organoids—A New Method to Characterize the Metabolism of Brain Organoids?" Pharmaceuticals 14, no. 9 (August 30, 2021): 878. http://dx.doi.org/10.3390/ph14090878.
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Organoids are a powerful tool in the quest to understand human diseases. As the developing brain is extremely inaccessible in mammals, cerebral organoids (COs) provide a unique way to investigate neural development and related disorders. The aim of this study was to utilize hyperpolarized 13C NMR to investigate the metabolism of COs in real-time, in a non-destructive manner. The enzymatic activity of lactate dehydrogenase (LDH) was determined by quantifying the rate of [1-13C]lactate production from hyperpolarized [1-13C]pyruvate. Organoid development was assessed by immunofluorescence imaging. Organoid viability was confirmed using 31P NMR spectroscopy. A total of 15 organoids collated into 3 groups with a group total weight of 20–77 mg were used in this study. Two groups were at the age of 10 weeks and one was at the age of 33 weeks. The feasibility of this approach was demonstrated in both age groups, and the LDH activity rate was found to be 1.32 ± 0.75 nmol/s (n = 3 organoid batches). These results suggest that hyperpolarized NMR can be used to characterize the metabolism of brain organoids with a total tissue wet weight of as low as 20 mg (<3 mm3) and a diameter ranging from 3 to 6 mm.
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Tomaskovic-Crook, Eva, Sarah Liza Higginbottom, Binbin Zhang, Justin Bourke, Gordon George Wallace, and Jeremy Micah Crook. "Defined, Simplified, Scalable, and Clinically Compatible Hydrogel-Based Production of Human Brain Organoids." Organoids 2, no. 1 (January 11, 2023): 20–36. http://dx.doi.org/10.3390/organoids2010002.
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Human brain organoids present a new paradigm for modeling human brain organogenesis, providing unprecedented insight to the molecular and cellular processes of brain development and maturation. Other potential applications include in vitro models of disease and tissue trauma, as well as three-dimensional (3D) clinically relevant tissues for pharmaceuticals development and cell or tissue replacement. A key requirement for this emerging technology in both research and medicine is the simple, scalable, and reproducible generation of organoids using reliable, economical, and high-throughput culture platforms. Here we describe such a platform using a defined, clinically compliant, and readily available hydrogel generated from gelatin methacrylate (GelMA). We demonstrate the efficient production of organoids on GelMA from human induced pluripotent stem cells (iPSCs), with scalable production attained using 3D printed GelMA-based multiwell arrays. The differentiation of iPSCs was systematic, rapid, and direct to enable iPSCs to form organoids in their original position following seeding on GelMA, thereby avoiding further cell and organoid disruption. Early neural precursors formed by day 5, neural rosettes and early-stage neurons by day 14, and organoids with cellular and regional heterogeneity, including mature and electrophysiologically active neurons, by day 28. The optimised method provides a simplified and well-defined platform for both research and translation of iPSCs and derivative brain organoids, enabling reliable 3D in vitro modelling and experimentation, as well as the provision of clinically relevant cells and tissues for future therapeutics.
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Carpena, Nathaniel T., So-Young Chang, Ji-Eun Choi, Jae Yun Jung, and Min Young Lee. "Wnt Modulation Enhances Otic Differentiation by Facilitating the Enucleation Process but Develops Unnecessary Cardiac Structures." International Journal of Molecular Sciences 22, no. 19 (September 24, 2021): 10306. http://dx.doi.org/10.3390/ijms221910306.
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Otic organoids have the potential to resolve current challenges in hearing loss research. The reproduction of the delicate and complex structure of the mammalian cochlea using organoids requires high efficiency and specificity. Recent attempts to strengthen otic organoids have focused on the effects of the Wnt signaling pathway on stem cell differentiation. One important aspect of this is the evaluation of undesirable effects of differentiation after Wnt activation. In the present study, we differentiated mouse embryonic stem cell embryoid bodies (EB) into otic organoids and observed two morphologies with different cell fates. EBs that underwent a core ejection process, or ‘enucleation,’ were similar to previously reported inner ear organoids. Meanwhile, EBs that retained their core demonstrated features characteristic of neural organoids. The application of a Wnt agonist during the maturation phase increased enucleation, as well as otic organoid formation, in turn leading to sensory hair cell-like cell generation. However, with a longer incubation period, Wnt activation also led to EBs with ‘beating’ organoids that exhibited spontaneous movement. This observation emphasizes the necessity of optimizing Wnt enhancement for the differentiation of specific cells, such as those found in the inner ear.
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Revah, Omer, Felicity Gore, Kevin W. Kelley, Jimena Andersen, Noriaki Sakai, Xiaoyu Chen, Min-Yin Li, et al. "Maturation and circuit integration of transplanted human cortical organoids." Nature 610, no. 7931 (October 12, 2022): 319–26. http://dx.doi.org/10.1038/s41586-022-05277-w.
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AbstractSelf-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1–5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
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Peterson, James C. "Evangelicals, Neural Organoids, and Chimeras." Perspectives on Science and Christian Faith 73, no. 1 (March 2021): 1–3. http://dx.doi.org/10.56315/pscf3-21peterson.
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Han, Yilin, Marianne King, Evgenii Tikhomirov, Povilas Barasa, Cleide Dos Santos Souza, Jonas Lindh, Daiva Baltriukiene, et al. "Towards 3D Bioprinted Spinal Cord Organoids." International Journal of Molecular Sciences 23, no. 10 (May 21, 2022): 5788. http://dx.doi.org/10.3390/ijms23105788.
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Three-dimensional (3D) cultures, so-called organoids, have emerged as an attractive tool for disease modeling and therapeutic innovations. Here, we aim to determine if boundary cap neural crest stem cells (BC) can survive and differentiate in gelatin-based 3D bioprinted bioink scaffolds in order to establish an enabling technology for the fabrication of spinal cord organoids on a chip. BC previously demonstrated the ability to support survival and differentiation of co-implanted or co-cultured cells and supported motor neuron survival in excitotoxically challenged spinal cord slice cultures. We tested different combinations of bioink and cross-linked material, analyzed the survival of BC on the surface and inside the scaffolds, and then tested if human iPSC-derived neural cells (motor neuron precursors and astrocytes) can be printed with the same protocol, which was developed for BC. We showed that this protocol is applicable for human cells. Neural differentiation was more prominent in the peripheral compared to central parts of the printed construct, presumably because of easier access to differentiation-promoting factors in the medium. These findings show that the gelatin-based and enzymatically cross-linked hydrogel is a suitable bioink for building a multicellular, bioprinted spinal cord organoid, but that further measures are still required to achieve uniform neural differentiation.
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Riedel, Nicole, Flavia W. De Faria, Carolin Walter, Jan M. Bruder, and Kornelius Kerl. "MODL-10. Tumor-brain-organoids as a model for pediatric brain tumors research." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i170. http://dx.doi.org/10.1093/neuonc/noac079.633.
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Abstract BACKGROUND: Embryonal brain neoplasms like atypical teratoid rhabdoid tumor (ATRT) or embryonal tumor with multilayered rosettes (ETMR) still have a very poor outcome despite intensive treatment including chemotherapy, irradiation and surgery. To date, precision oncology has identified clinically relevant innovative therapeutic targets only for a minor subpopulation of pediatric brain tumor patients, which may be due to current in vitro screens not recapitulating the cellular heterogeneity and cellular interactions in vivo. As cellular heterogeneity and cellular interactions majorly influence the response of tumor cells to treatment, we established an innovative 3D screening platform that combines human neural tissue surrounding primary tumor tissue. METHODS: We established a model of tumor-brain-organoids (TBO) by incorporating embryonal tumor cells (ATRT and ETMR tumor cells) into hiPSC-derived forebrain organoids. Using whole mount immunostaining (WMI), we evaluated cancer-phenotype, the neuronal and progenitor cell distribution in brain organoids, and we performed drug screening analysis. Furthermore, we used single-cell RNA-sequencing to characterize the cellular heterogeneity and the effect of tumor-organoid cell-cell communication on transcriptional programs. RESULTS: ATRT as well as ETMR tumor cells incorporated extensively into the organoid tissue. We observed remarkable differences in the invasiveness of ATRT-MYC cells into TBO in comparison with ATRT-SHH and ETMR cells via high content imaging. Moreover, tumor cells affected the gene expression of different cell types of the organoid by upregulating genes of important signaling/growth related pathways (e. g. MAP2K2, IGFBP2) and epigenetic regulators (like BRD7). Screening through a 300 compound FDA-approved drug library in these TBO, we identified potential innovative therapeutic approaches against these embryonal tumors. CONCLUSION: Tumor-brain-organoids can be used as a platform to study tumor biology, tumor interactions with its neural tissue microenvironment, as well as for high-throughput drug and toxicity screening in pediatric brain tumor precision oncology.
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Conforti, P., D. Besusso, V. D. Bocchi, A. Faedo, E. Cesana, G. Rossetti, V. Ranzani, et al. "Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes." Proceedings of the National Academy of Sciences 115, no. 4 (January 8, 2018): E762—E771. http://dx.doi.org/10.1073/pnas.1715865115.
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Increasing evidence suggests that early neurodevelopmental defects in Huntington’s disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.
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Layrolle, Pierre, Pierre Payoux, and Stéphane Chavanas. "Message in a Scaffold: Natural Biomaterials for Three-Dimensional (3D) Bioprinting of Human Brain Organoids." Biomolecules 13, no. 1 (December 22, 2022): 25. http://dx.doi.org/10.3390/biom13010025.
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Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the limitations of self-organized organoids. It requires the development of optimal hydrogels, and a wealth of research has improved our knowledge about biomaterials both in terms of their intrinsic properties and their relevance on 3D culture of brain cells and tissue. Although biomaterials are rarely biologically neutral, few articles have reviewed their roles on neural cells. We here review the current knowledge on unmodified biomaterials amenable to support 3D bioprinting of neural organoids with a particular interest in their impact on cell homeostasis. Alginate is a particularly suitable bioink base for cell encapsulation. Gelatine is a valuable helper agent for 3D bioprinting due to its viscosity. Collagen, fibrin, hyaluronic acid and laminin provide biological support to adhesion, motility, differentiation or synaptogenesis and optimize the 3D culture of neural cells. Optimization of specialized hydrogels to direct differentiation of stem cells together with an increased resolution in phenotype analysis will further extend the spectrum of possible bioprinted brain disease models.
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Matsui, Takeshi K., Yuichiro Tsuru, Koichi Hasegawa, and Ken-ichiro Kuwako. "Vascularization of Human Brain Organoids." Stem Cells 39, no. 8 (March 31, 2021): 1017–24. http://dx.doi.org/10.1002/stem.3368.
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Abstract Human brain organoids are three-dimensional tissues that are generated in vitro from pluripotent stem cells and recapitulate the early development of the human brain. Brain organoids consist mainly of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes, and oligodendrocytes. However, all human brain organoids lack vasculature, which plays indispensable roles not only in brain homeostasis but also in brain development. In addition to the delivery of oxygen and nutrition, accumulating evidence suggests that the vascular system of the brain regulates neural differentiation, migration, and circuit formation during development. Therefore, vascularization of human brain organoids is of great importance. Current trials to vascularize various organoids include the adjustment of cultivation protocols, the introduction of microfluidic devices, and the transplantation of organoids into immunodeficient mice. In this review, we summarize the efforts to accomplish vascularization and perfusion of brain organoids, and we discuss these attempts from a forward-looking perspective.
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Zhang, Ru, Juan Lu, Gang Pei, and Shichao Huang. "Galangin Rescues Alzheimer’s Amyloid-β Induced Mitophagy and Brain Organoid Growth Impairment." International Journal of Molecular Sciences 24, no. 4 (February 8, 2023): 3398. http://dx.doi.org/10.3390/ijms24043398.
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Dysfunctional mitochondria and mitophagy are hallmarks of Alzheimer’s disease (AD). It is widely accepted that restoration of mitophagy helps to maintain cellular homeostasis and ameliorates the pathogenesis of AD. It is imperative to create appropriate preclinical models to study the role of mitophagy in AD and to assess potential mitophagy-targeting therapies. Here, by using a novel 3D human brain organoid culturing system, we found that amyloid-β (Aβ1-42,10 μM) decreased the growth level of organoids, indicating that the neurogenesis of organoids may be impaired. Moreover, Aβ treatment inhibited neural progenitor cell (NPC) growth and induced mitochondrial dysfunction. Further analysis revealed that mitophagy levels were reduced in the brain organoids and NPCs. Notably, galangin (10 μM) treatment restored mitophagy and organoid growth, which was inhibited by Aβ. The effect of galangin was blocked by the mitophagy inhibitor, suggesting that galangin possibly acted as a mitophagy enhancer to ameliorate Aβ-induced pathology. Together, these results supported the important role of mitophagy in AD pathogenesis and suggested that galangin may be used as a novel mitophagy enhancer to treat AD.
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Delepine, Chloe, Vincent A. Pham, Hayley W. S. Tsang, and Mriganka Sur. "GSK3ß inhibitor CHIR 99021 modulates cerebral organoid development through dose-dependent regulation of apoptosis, proliferation, differentiation and migration." PLOS ONE 16, no. 5 (May 5, 2021): e0251173. http://dx.doi.org/10.1371/journal.pone.0251173.
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Cerebral organoids generated from human pluripotent stem cells (hiPSCs) are unique in their ability to recapitulate human-specific neurodevelopmental events. They are capable of modeling the human brain and its cell composition, including human-specific progenitor cell types; ordered laminar compartments; and both cell-specific transcriptional signatures and the broader telencephalic transcriptional landscape. The serine/threonine kinase, GSK3β, plays a critical role in neurodevelopment, controlling processes as varied as neurogenesis, morphological changes, polarization, and migration. In the generation of cerebral organoids, inhibition of GSK3β at low doses has been used to increase organoid size and decrease necrotic core. However, little is known of the effects of GSK3β inhibition on organoid development. Here, we demonstrate that while low dose of GSK3β inhibitor CHIR 99021 increases organoid size, higher dose actually reduces organoid size; with the highest dose arresting organoid growth. To examine the mechanisms that may contribute to the phenotypic size differences observed in these treatment groups, we show that low dose of CHIR 99021 increases cell survival, neural progenitor cell proliferation and neuronal migration. A higher dose, however, decreases not only apoptosis but also proliferation, and arrests neural differentiation, enriching the pool of neuroepithelial cells, and decreasing the pools of early neuronal progenitors and neurons. These results reveal new mechanisms of the pleiotropic effects of GSK3β during organoid development, providing essential information for the improvement of organoid production and ultimately shedding light on the mechanisms of embryonic brain development.
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Bombieri, Cristina, Andrea Corsi, Elisabetta Trabetti, Alessandra Ruggiero, Giulia Marchetto, Gaetano Vattemi, Maria Teresa Valenti, Donato Zipeto, and Maria Grazia Romanelli. "Advanced Cellular Models for Rare Disease Study: Exploring Neural, Muscle and Skeletal Organoids." International Journal of Molecular Sciences 25, no. 2 (January 13, 2024): 1014. http://dx.doi.org/10.3390/ijms25021014.
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Organoids are self-organized, three-dimensional structures derived from stem cells that can mimic the structure and physiology of human organs. Patient-specific induced pluripotent stem cells (iPSCs) and 3D organoid model systems allow cells to be analyzed in a controlled environment to simulate the characteristics of a given disease by modeling the underlying pathophysiology. The recent development of 3D cell models has offered the scientific community an exceptionally valuable tool in the study of rare diseases, overcoming the limited availability of biological samples and the limitations of animal models. This review provides an overview of iPSC models and genetic engineering techniques used to develop organoids. In particular, some of the models applied to the study of rare neuronal, muscular and skeletal diseases are described. Furthermore, the limitations and potential of developing new therapeutic approaches are discussed.
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Kanber, Deniz, Julia Woestefeld, Hannah Döpper, Morgane Bozet, Alexandra Brenzel, Janine Altmüller, Fabian Kilpert, Dietmar Lohmann, Claudia Pommerenke, and Laura Steenpass. "RB1-Negative Retinal Organoids Display Proliferation of Cone Photoreceptors and Loss of Retinal Differentiation." Cancers 14, no. 9 (April 26, 2022): 2166. http://dx.doi.org/10.3390/cancers14092166.
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Retinoblastoma is a tumor of the eye in children under the age of five caused by biallelic inactivation of the RB1 tumor suppressor gene in maturing retinal cells. Cancer models are essential for understanding tumor development and in preclinical research. Because of the complex organization of the human retina, such models were challenging to develop for retinoblastoma. Here, we present an organoid model based on differentiation of human embryonic stem cells into neural retina after inactivation of RB1 by CRISPR/Cas9 mutagenesis. Wildtype and RB1 heterozygous mutant retinal organoids were indistinguishable with respect to morphology, temporal development of retinal cell types and global mRNA expression. However, loss of pRB resulted in spatially disorganized organoids and aberrant differentiation, indicated by disintegration of organoids beyond day 130 of differentiation and depletion of most retinal cell types. Only cone photoreceptors were abundant and continued to proliferate, supporting these as candidate cells-of-origin for retinoblastoma. Transcriptome analysis of RB1 knockout organoids and primary retinoblastoma revealed gain of a retinoblastoma expression signature in the organoids, characterized by upregulation of RBL1 (p107), MDM2, DEK, SYK and HELLS. In addition, genes related to immune response and extracellular matrix were specifically upregulated in RB1-negative organoids. In vitro retinal organoids therefore display some features associated with retinoblastoma and, so far, represent the only valid human cancer model for the development of this disease.
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Mukashyaka, Patience, Pooja Kumar, David J. Mellert, Shadae Nicholas, Javad Noorbakhsh, Mattia Brugiolo, Olga Anczukow, Edison T. Liu, and Jeffrey H. Chuang. "Abstract A032: Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): A032. http://dx.doi.org/10.1158/1538-7445.canevol23-a032.
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Abstract Three-dimensional (3D) culture models, such as organoids, are flexible systems to interrogate cellular evolution, cellular growth and morphology, multicellular spatial architecture, and cell interactions in response to drug treatment. However, new computational methods to segment and analyze 3D models at cellular resolution with sufficiently high throughput are needed to realize these possibilities. Here we report Cellos (Cell and Organoid Segmentation), an accurate, high throughput image analysis pipeline for 3D organoid and nuclear segmentation analysis. Cellos segments organoids in 3D using classical algorithms and segments nuclei using a Stardist-3D convolutional neural network which we trained on manually annotated dataset of 3,862 cells. To evaluate the capabilities of Cellos we then analyzed 74,450 organoids with 1.65 million cells, from multiple experiments on triple negative breast cancer organoids containing clonal mixtures with complex cisplatin sensitivies. Cellos was able to accurately distinguish ratios of distinct fluorescently labeled cell populations in organoids, with < 3% deviation from seeding ratios in each well and was effective for both fluorescently labelled nuclei and independent Hoechst stained datasets. Cellos was able to recapitulate traditional luminescence-based drug response quantification by analyzing 3D images, including parallel analysis of multiple cancer clones in the same well. Moreover, Cellos was able to identify organoid and nuclei morphology features associated with treatment and unique to each of the clones. Finally, Cellos enables 3D analysis of cell spatial relationships, which we used to detect ecological affinity between cancer clones beyond what arises from local cell division and organoid composition. Cellos provides powerful tools to perform high throughput analysis for pharmacological testing and biological investigation of organoids based on 3D imaging. Citation Format: Patience Mukashyaka, Pooja Kumar, David J. Mellert, Shadae Nicholas, Javad Noorbakhsh, Mattia Brugiolo, Olga Anczukow, Edison T. Liu, Jeffrey H. Chuang. Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A032.
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Wörsdörfer, Philipp, Takashi I, Izumi Asahina, Yoshinori Sumita, and Süleyman Ergün. "Do not keep it simple: recent advances in the generation of complex organoids." Journal of Neural Transmission 127, no. 11 (May 8, 2020): 1569–77. http://dx.doi.org/10.1007/s00702-020-02198-8.
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Abstract 3D cell culture models which closely resemble real human tissues are of high interest for disease modelling, drug screening as well as a deeper understanding of human developmental biology. Such structures are termed organoids. Within the last years, several human organoid models were described. These are usually stem cell derived, arise by self-organization, mimic mechanisms of normal tissue development, show typical organ morphogenesis and recapitulate at least some organ specific functions. Many tissues have been reproduced in vitro such as gut, liver, lung, kidney and brain. The resulting entities can be either derived from an adult stem cell population, or generated from pluripotent stem cells using a specific differentiation protocol. However, many organoid models only recapitulate the organs parenchyma but are devoid of stromal components such as blood vessels, connective tissue and inflammatory cells. Recent studies show that the incorporation of endothelial and mesenchymal cells into organoids improved their maturation and might be required to create fully functional micro-tissues, which will allow deeper insights into human embryogenesis as well as disease development and progression. In this review article, we will summarize and discuss recent works trying to incorporate stromal components into organoids, with a special focus on neural organoid models.
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Mrza, Muhammad Asif, Jitian He, and Youwei Wang. "Integration of iPSC-Derived Microglia into Brain Organoids for Neurological Research." International Journal of Molecular Sciences 25, no. 6 (March 9, 2024): 3148. http://dx.doi.org/10.3390/ijms25063148.
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The advent of Induced Pluripotent Stem Cells (iPSCs) has revolutionized neuroscience research. This groundbreaking innovation has facilitated the development of three-dimensional (3D) neural organoids, which closely mimicked the intricate structure and diverse functions of the human brain, providing an unprecedented platform for the in-depth study and understanding of neurological phenomena. However, these organoids lack key components of the neural microenvironment, particularly immune cells like microglia, thereby limiting their applicability in neuroinflammation research. Recent advancements focused on addressing this gap by integrating iPSC-derived microglia into neural organoids, thereby creating an immunized microenvironment that more accurately reflects human central neural tissue. This review explores the latest developments in this field, emphasizing the interaction between microglia and neurons within immunized neural organoids and highlights how this integrated approach not only enhances our understanding of neuroinflammatory processes but also opens new avenues in regenerative medicine.
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Jones, Peter D., Tom Stumpp, Michael Mierzejewski, Domenic Pascual, and Angelika Stumpf. "Scalable mesh microelectrode arrays for neural spheroids and organoids." Current Directions in Biomedical Engineering 9, no. 1 (September 1, 2023): 575–78. http://dx.doi.org/10.1515/cdbme-2023-1144.
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Abstract Introduction: Neural organoids promise to help understand the human brain and develop treatments for neurological diseases. Electrophysiological recordings are essential in neural models to evaluate the activity of neural circuits. Mesh microelectrode arrays (MEAs) have been demonstrated to be suitable for organoids and spheroids, and there is demand for easy-to-use devices that can be manufactured at scale. Methods: We present a new mesh MEA device with an easyto- use design. We produce mesh MEA chips on 100 mm carrier wafers and connect individual chips to PCBs by wirebonding. The devices are completed by assembly of a twopiece well and a glass cover slip. Results: Each device contains a suspended hammock-like mesh with 64 microelectrodes. The square grid’s pitch of 200 μm makes the mesh suitable for typical organoid sizes while spreading the electrodes across a 1.4 mm region. The well is designed for fluid handling by pipetting or pump systems. Impedance measurements indicate a high yield of functional microelectrodes, although further effort is needed to produce consistent low impedances. The devices are compatible with commercial amplifiers, while adaptation of the PCB to other formats will be straightforward. Conclusions: Using scalable production methods, we have developed a mesh MEA device design that offers improved ease-of-use. Next steps will include biological validation in collaboration with partners.
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Birch, Jonathan, and Heather Browning. "Neural Organoids and the Precautionary Principle." American Journal of Bioethics 21, no. 1 (December 29, 2020): 56–58. http://dx.doi.org/10.1080/15265161.2020.1845858.
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LeMieux, Julianna. "Neural Organoids Making Connections, Getting Real." Genetic Engineering & Biotechnology News 42, no. 11 (November 1, 2022): 18–21. http://dx.doi.org/10.1089/gen.42.11.07.
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Yan, Yuanwei, Julie Bejoy, Mark Marzano, and Yan Li. "The Use of Pluripotent Stem Cell-Derived Organoids to Study Extracellular Matrix Development during Neural Degeneration." Cells 8, no. 3 (March 14, 2019): 242. http://dx.doi.org/10.3390/cells8030242.
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The mechanism that causes the Alzheimer’s disease (AD) pathologies, including amyloid plaque, neurofibrillary tangles, and neuron death, is not well understood due to the lack of robust study models for human brain. Three-dimensional organoid systems based on human pluripotent stem cells (hPSCs) have shown a promising potential to model neurodegenerative diseases, including AD. These systems, in combination with engineering tools, allow in vitro generation of brain-like tissues that recapitulate complex cell-cell and cell-extracellular matrix (ECM) interactions. Brain ECMs play important roles in neural differentiation, proliferation, neuronal network, and AD progression. In this contribution related to brain ECMs, recent advances in modeling AD pathology and progression based on hPSC-derived neural cells, tissues, and brain organoids were reviewed and summarized. In addition, the roles of ECMs in neural differentiation of hPSCs and the influences of heparan sulfate proteoglycans, chondroitin sulfate proteoglycans, and hyaluronic acid on the progression of neurodegeneration were discussed. The advantages that use stem cell-based organoids to study neural degeneration and to investigate the effects of ECM development on the disease progression were highlighted. The contents of this article are significant for understanding cell-matrix interactions in stem cell microenvironment for treating neural degeneration.
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Ferdaos, Nurfarhana, Sally Lowell, and John O. Mason. "Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains." PLOS ONE 17, no. 11 (November 28, 2022): e0278147. http://dx.doi.org/10.1371/journal.pone.0278147.
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Cerebral organoids show great promise as tools to unravel the complex mechanisms by which the mammalian brain develops during embryogenesis. We generated mouse cerebral organoids harbouring constitutive or conditional mutations in Pax6, which encodes a transcription factor with multiple important roles in brain development. By comparing the phenotypes of mutant organoids with the well-described phenotypes of Pax6 mutant mouse embryos, we evaluated the extent to which cerebral organoids reproduce phenotypes previously described in vivo. Organoids lacking Pax6 showed multiple phenotypes associated with its activity in mice, including precocious neural differentiation, altered cell cycle and an increase in abventricular mitoses. Neural progenitors in both Pax6 mutant and wild type control organoids cycled more slowly than their in vivo counterparts, but nonetheless we were able to identify clear changes to cell cycle attributable to the absence of Pax6. Our findings support the value of cerebral organoids as tools to explore mechanisms of brain development, complementing the use of mouse models.
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Costamagna, Gianluca, Giacomo Pietro Comi, and Stefania Corti. "Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids." International Journal of Molecular Sciences 22, no. 5 (March 6, 2021): 2659. http://dx.doi.org/10.3390/ijms22052659.
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In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.
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Blue, Rachel, Stephen P. Miranda, Ben Jiahe Gu, and H. Isaac Chen. "A Primer on Human Brain Organoids for the Neurosurgeon." Neurosurgery 87, no. 4 (May 18, 2020): 620–29. http://dx.doi.org/10.1093/neuros/nyaa171.
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Abstract Human brain organoids emerged in 2013 as a technology that, unlike prior in Vitro neural models, recapitulates brain development with a high degree of spatial and temporal fidelity. As the platform matured with more accurate reproduction of cerebral architecture, brain organoids became increasingly valuable for studying both normal cortical neurogenesis and a variety of congenital human brain disorders. While the majority of research utilizing human brain organoids has been in the realm of basic science, clinical applications are forthcoming. These present and future translational efforts have the potential to make a considerable impact on the field of neurosurgery. For example, glioma organoids are already being used to study tumor biology and drug responses, and adaptation for the investigation of other neurosurgery-relevant diseases is underway. Moreover, organoids are being explored as a structured neural substrate for repairing brain circuitry. Thus, we believe it is important for our field to be aware and have an accurate understanding of this emerging technology. In this review, we describe the key characteristics of human brain organoids, review their relevant translational applications, and discuss the ethical implications of their use through a neurosurgical lens.
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Khare, Sonal, Chi-Sing Ho, Madhavi Kannan, Brian Larsen, Brandon Mapes, Jenna Shaxted, Jagadish Venkataraman, and Ameen Salahudeen. "62 Applying machine vision to empower preclinical development of cell engager and adoptive cell therapeutics in patient-derived organoid models of solid tumors." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A70. http://dx.doi.org/10.1136/jitc-2021-sitc2021.062.
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BackgroundCell engager and adoptive cell therapeutics have emerged as efficacious and durable treatments in patients with B-cell malignancies. Though many analogous strategies are under development in solid tumors, none have received approval. Preclinical development of these therapies requires cell labeling of immortalized cell lines and/or primary expanded T cells to distinguish target and effector cells. However, cell engager and adoptive cell therapies have had limited evidence of reproducibility in primary patient-derived models such as tumor organoid cultures thus far. Here, we build upon our tumor organoid platform1 to measure organoid specific responses to these therapies. Utilizing machine vision coupled with time-lapse-microscopy, we obtain multiparameter kinetic readouts of patient-derived tumor organoid cell killing and allogeneic MHC-matched primary peripheral blood mononuclear cells (PBMCs).MethodsThe patient-derived tumor organoids were co-cultured with PBMCs in the presence of engagers/activators and vital dyes and incubated for 96 hrs. Cell death was measured by quantifying the caspase 3/7 vital dye pixel intensities at different time points using high throughput imaging. As a first step, a fully convolutional neural network was trained to segment out organoids from brightfield images comprised of organoids, immune cells and potential background artifacts. This segmentation mask was then transferred over to registered caspase 3/7 images to quantify tumor cell specific phenotypes in a rapid and automated manner.ResultsThe time-lapse imaging assay allowed for both the tracking of the organoid growth over time as well as the quantification of the kinetics of engagers/activators in comparison to controls resulting in accurate and precise technical reproducibility. Further, this assay allowed for the co-localization of the organoids and the immune cells over time, thus, enabling a spatiotemporal summary of dose dependent efficacy of candidate therapeutics.ConclusionsWe demonstrate the scalability and throughput of a machine vision tumor organoid immune co-culture platform across multiple unique patient-derived tumor organoid lines bearing a target of interest, enabling future discovery of biomarkers of therapeutic response and resistance.ReferenceLarsen B, Kannan M, Langer LF, Khan AA, Salahudeen AA, A pan-cancer organoid platform for precision medicine. Cell Reports 2021; 36:109429
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D’Aiuto, Leonardo, Jill K. Caldwell, Callen T. Wallace, Tristan R. Grams, Maribeth A. Wesesky, Joel A. Wood, Simon C. Watkins, Paul R. Kinchington, David C. Bloom, and Vishwajit L. Nimgaonkar. "The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids." Cells 11, no. 22 (November 9, 2022): 3539. http://dx.doi.org/10.3390/cells11223539.
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Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.
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Rockel, Anna F., Süleyman Ergün, and Philipp Wörsdörfer. "Erzeugung menschlicher Nervengewebe in der Kulturschale." BIOspektrum 29, no. 7 (November 2023): 752–54. http://dx.doi.org/10.1007/s12268-023-2063-z.
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AbstractMultiple protocols for organoid models of the human brain were developed over the last decade, representing different brain regions. Co-cultures of these organoids, referred to as assembloids, have further increased the complexity of these cultures. Our lab is working on neuro-mesodermal assembloids, which show incorporation of blood vessels and microglia-like cells into the nervous tissue. Moreover, these assembloids also contain neural crest cells and show peripheral nervous system development.
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Li, Minghui, Heng Sun, Zongkun Hou, Shilei Hao, Liang Jin, and Bochu Wang. "Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment." Small, September 28, 2023. http://dx.doi.org/10.1002/smll.202306451.
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AbstractUnderstanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell‐derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting‐edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid‐based research and neuroscience.
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Osaki, Tatsuya, Tomoya Duenki, Siu Yu A. Chow, Yasuhiro Ikegami, Romain Beaubois, Timothée Levi, Nao Nakagawa-Tamagawa, Yoji Hirano, and Yoshiho Ikeuchi. "Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons." Nature Communications 15, no. 1 (April 10, 2024). http://dx.doi.org/10.1038/s41467-024-46787-7.
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AbstractAn inter-regional cortical tract is one of the most fundamental architectural motifs that integrates neural circuits to orchestrate and generate complex functions of the human brain. To understand the mechanistic significance of inter-regional projections on development of neural circuits, we investigated an in vitro neural tissue model for inter-regional connections, in which two cerebral organoids are connected with a bundle of reciprocally extended axons. The connected organoids produced more complex and intense oscillatory activity than conventional or directly fused cerebral organoids, suggesting the inter-organoid axonal connections enhance and support the complex network activity. In addition, optogenetic stimulation of the inter-organoid axon bundles could entrain the activity of the organoids and induce robust short-term plasticity of the macroscopic circuit. These results demonstrated that the projection axons could serve as a structural hub that boosts functionality of the organoid-circuits. This model could contribute to further investigation on development and functions of macroscopic neuronal circuits in vitro.
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Majumder, Joydeb, Elizabeth E. Torr, Elizabeth A. Aisenbrey, Connie S. Lebakken, Peter F. Favreau, William D. Richards, Yanhong Yin, Qiang Chang, and William L. Murphy. "Human induced pluripotent stem cell-derived planar neural organoids assembled on synthetic hydrogels." Journal of Tissue Engineering 15 (January 2024). http://dx.doi.org/10.1177/20417314241230633.
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The tailorable properties of synthetic polyethylene glycol (PEG) hydrogels make them an attractive substrate for human organoid assembly. Here, we formed human neural organoids from iPSC-derived progenitor cells in two distinct formats: (i) cells seeded on a Matrigel surface; and (ii) cells seeded on a synthetic PEG hydrogel surface. Tissue assembly on synthetic PEG hydrogels resulted in three dimensional (3D) planar neural organoids with greater neuronal diversity, greater expression of neurovascular and neuroinflammatory genes, and reduced variability when compared with tissues assembled upon Matrigel. Further, our 3D human tissue assembly approach occurred in an open cell culture format and created a tissue that was sufficiently translucent to allow for continuous imaging. Planar neural organoids formed on PEG hydrogels also showed higher expression of neural, vascular, and neuroinflammatory genes when compared to traditional brain organoids grown in Matrigel suspensions. Further, planar neural organoids contained functional microglia that responded to pro-inflammatory stimuli, and were responsive to anti-inflammatory drugs. These results demonstrate that the PEG hydrogel neural organoids can be used as a physiologically relevant in vitro model of neuro-inflammation.