Journal articles: 'Cortical organoids'

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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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Yang, Woo Sub, Ferdi Ridvan Kiral, and In-Hyun Park. "Telencephalic organoids as model systems to study cortical development and diseases." Organoid 4 (January 25, 2024): e1. http://dx.doi.org/10.51335/organoid.2024.4.e1.

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The telencephalon is the largest region of the brain and processes critical brain activity. Despite much progress, our understanding of the telencephalon’s function, development, and pathophysiological processes remains largely incomplete. Recently, 3-dimensional brain models, known as brain organoids, have attracted considerable attention in modern neurobiological research. Brain organoids have been proven to be valuable for studying the neurodevelopmental principles and pathophysiology of the brain, as well as for developing potential therapeutics. Brain organoids can change the paradigm of current research, replacing animal models. However, there are still limitations, and efforts are needed to improve brain organoid models. In this review, we provide an overview of the development and function of the telencephalon, as well as the techniques and scientific methods used to create fully developed telencephalon organoids. Additionally, we explore the limitations and challenges of current brain organoids and potential future advancements.

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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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Farcy, Sarah, Alexandra Albert, Pierre Gressens, Alexandre D. Baffet, and Vincent El Ghouzzi. "Cortical Organoids to Model Microcephaly." Cells 11, no. 14 (July 7, 2022): 2135. http://dx.doi.org/10.3390/cells11142135.

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How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man’s place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.

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Bray, Natasha. "Inroads into cortical organoids." Nature Reviews Neuroscience 20, no. 12 (October 16, 2019): 717. http://dx.doi.org/10.1038/s41583-019-0237-y.

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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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Chandrasegaran, Praveena, Agatha Nabilla Lestari, Matthew C. Sinton, Jay Gopalakrishnan, and Juan F. Quintana. "Modelling host-Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids." F1000Research 12 (July 28, 2023): 437. http://dx.doi.org/10.12688/f1000research.131507.2.

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Background: Sleeping sickness is caused by the extracellular parasite Trypanosoma brucei and is associated with neuroinflammation and neuropsychiatric disorders, including disruption of sleep/wake patterns, and is now recognised as a circadian disorder. Sleeping sickness is traditionally studied using murine models of infection due to the lack of alternative in vitro systems that fully recapitulate the cellular diversity and functionality of the human brain. The aim of this study is to develop a much-needed in vitro system that reduces and replaces live animals for the study of infections in the central nervous system, using sleeping sickness as a model infection. Methods: We developed a co-culture system using induced pluripotent stem cell (iPSC)-derived cortical human brain organoids and the human pathogen T. b. gambiense to model host-pathogen interactions in vitro. Upon co-culture, we analysed the transcriptional responses of the brain organoids to T. b. gambiense over two time points. Results: We detected broad transcriptional changes in brain organoids exposed to T. b. gambiense, mainly associated with innate immune responses, chemotaxis, and blood vessel differentiation compared to untreated organoids. Conclusions: Our co-culture system provides novel, more ethical avenues to study host-pathogen interactions in the brain as alternative models to experimental infections in mice. Although our data support the use of brain organoids to model host-pathogen interactions during T. brucei infection as an alternative to in vivo models, future work is required to increase the complexity of the organoids ( e.g., addition of microglia and vasculature). We envision that the adoption of organoid systems is beneficial to researchers studying mechanisms of brain infection by protozoan parasites. Furthermore, organoid systems have the potential to be used to study other parasites that affect the brain significantly reducing the number of animals undergoing moderate and/or severe protocols associated with the study of neuroinflammation and brain infections.

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Li, Xiaodong, Abdullah Shopit, and Jingmin Wang. "A Comprehensive Update of Cerebral Organoids between Applications and Challenges." Oxidative Medicine and Cellular Longevity 2022 (December 5, 2022): 1–10. http://dx.doi.org/10.1155/2022/7264649.

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The basic technology of stem cells has been developed and created organoids, which have established a strong interest in regenerative medicine. Different cell types have been used to generate cerebral organoids, which include interneurons and oligodendrocytes (OLs). OLs are fundamental for brain development. Abundant studies have displayed that brain organoids can recapitulate fundamental and vital features of the human brain, such as cellular regulation and distribution, neuronal networks, electrical activities, and physiological structure. The organoids contain essential ventral brain domains and functional cortical interneurons, which are similar to the developing cortex and medial ganglionic eminence (MGE). So, brain organoids have provided a singular model to study and investigate neurological disorder mechanisms and therapeutics. Furthermore, the blood brain barrier (BBB) organoids modeling contributes to accelerate therapeutic discovery for the treatment of several neuropathologies. In this review, we summarized the advances of the brain organoids applications to investigate neurological disorder mechanisms such as neurodevelopmental and neurodegenerative disorders, mental disorders, brain cancer, and cerebral viral infections. We discussed brain organoids’ therapeutic application as a potential therapeutic unique method and highlighted in detail the challenges and hurdles of organoid models.

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Magni, Manuela, Beatrice Bossi, Paola Conforti, Maura Galimberti, Fabio Dezi, Tiziana Lischetti, Xiaoling He, et al. "Brain Regional Identity and Cell Type Specificity Landscape of Human Cortical Organoid Models." International Journal of Molecular Sciences 23, no. 21 (October 29, 2022): 13159. http://dx.doi.org/10.3390/ijms232113159.

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In vitro models of corticogenesis from pluripotent stem cells (PSCs) have greatly improved our understanding of human brain development and disease. Among these, 3D cortical organoid systems are able to recapitulate some aspects of in vivo cytoarchitecture of the developing cortex. Here, we tested three cortical organoid protocols for brain regional identity, cell type specificity and neuronal maturation. Overall, all protocols gave rise to organoids that displayed a time-dependent expression of neuronal maturation genes such as those involved in the establishment of synapses and neuronal function. Comparatively, guided differentiation methods without WNT activation generated the highest degree of cortical regional identity, whereas default conditions produced the broadest range of cell types such as neurons, astrocytes and hematopoietic-lineage-derived microglia cells. These results suggest that cortical organoid models produce diverse outcomes of brain regional identity and cell type specificity and emphasize the importance of selecting the correct model for the right application.

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Chandrasegaran, Praveena, Agatha Nabilla Lestari, Matthew C. Sinton, Jay Gopalakrishnan, and Juan F. Quintana. "Modelling host-Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids." F1000Research 12 (April 24, 2023): 437. http://dx.doi.org/10.12688/f1000research.131507.1.

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Background: Sleeping sickness is caused by the extracellular parasite Trypanosoma brucei and is associated with neuroinflammation and neuropsychiatric disorders, including disruption of sleep/wake patterns, and is now recognised as a circadian disorder. Sleeping sickness is traditionally studied using murine models of infection due to the lack of alternative in vitro systems that fully recapitulate the cellular diversity and functionality of the human brain. The aim of this study is to develop a much-needed in vitro system that reduces and replaces live animals for the study of infections in the central nervous system, using sleeping sickness as a model infection. Methods: We developed a co-culture system using induced pluripotent stem cell (iPSC)-derived cortical human brain organoids and the human pathogen T. b. gambiense to model host-pathogen interactions in vitro. Upon co-culture, we analysed the transcriptional responses of the brain organoids to T. b. gambiense over two time points. Results: We detected broad transcriptional changes in brain organoids exposed to T. b. gambiense, mainly associated with innate immune responses, chemotaxis, and blood vessel differentiation compared to untreated organoids. Conclusions: Our co-culture system provides novel, more ethical avenues to study host-pathogen interactions in the brain as alternative models to experimental infections in mice. Future work is required to increase the complexity of the organoids (e.g., addition of microglia and vasculature). We envision that the adoption of organoid systems will be beneficial to researchers studying mechanisms of brain infection by protozoan parasites. Furthermore, organoid systems have the potential to be used to study other parasites that affect the brain, including neurocysticercosis, significantly reducing the number of animals undergoing moderate and/or severe protocols associated with the study of neuroinflammation and brain infections.

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Sivitilli, Adam A., Jessica T. Gosio, Bibaswan Ghoshal, Alesya Evstratova, Daniel Trcka, Parisa Ghiasi, J. Javier Hernandez, Jean Martin Beaulieu, Jeffrey L. Wrana, and Liliana Attisano. "Robust production of uniform human cerebral organoids from pluripotent stem cells." Life Science Alliance 3, no. 5 (April 17, 2020): e202000707. http://dx.doi.org/10.26508/lsa.202000707.

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Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human-specific cortical development and pathophysiology in an experimentally tractable system. Although diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we have directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent hCOs and achieve a success rate of >80%. These hCOs include both a radial glial stem cell compartment and electrophysiologically competent mature neurons. Moreover, we show using immunofluorescence microscopy and single-cell profiling that individual organoids display reproducible cell type compositions that are conserved upon extended culture. We expect that application of this method will provide new insights into brain development and disease processes.

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Forero-Zapata, Laura, Ariel Lee, Alysson Muotri, Cedric Snethlage, Jon A. Gangoiti, and Bruce A. Barshop. "METABOLOMIC STUDIES IN CORTICAL BRAIN ORGANOIDS." Molecular Genetics and Metabolism 135, no. 4 (April 2022): 271. http://dx.doi.org/10.1016/j.ymgme.2022.01.038.

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Harrison, Charlotte. "Cortical organoids make mouse–human connections." Lab Animal 52, no. 2 (February 2023): 33. http://dx.doi.org/10.1038/s41684-023-01116-1.

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Marsoner, Fabio, Philipp Koch, and Julia Ladewig. "Cortical organoids: why all this hype?" Current Opinion in Genetics & Development 52 (October 2018): 22–28. http://dx.doi.org/10.1016/j.gde.2018.04.008.

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Rosebrock, Daniel, Sneha Arora, Naresh Mutukula, Rotem Volkman, Elzbieta Gralinska, Anastasios Balaskas, Amèlia Aragonés Hernández, et al. "Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells." Nature Cell Biology 24, no. 6 (June 2022): 981–95. http://dx.doi.org/10.1038/s41556-022-00929-5.

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AbstractCerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently suppressing non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC-specification capacity. Accordingly, this method selectively enriches for outer radial glia NSCs, which cyto-architecturally demarcate well-defined outer sub-ventricular-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD and WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring of fundamental molecular and cyto-architectural features of cortical development and meaningful disease modelling.

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Shi, Yingchao, Le Sun, Mengdi Wang, Jianwei Liu, Suijuan Zhong, Rui Li, Peng Li, et al. "Vascularized human cortical organoids (vOrganoids) model cortical development in vivo." PLOS Biology 18, no. 5 (May 13, 2020): e3000705. http://dx.doi.org/10.1371/journal.pbio.3000705.

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Qian, Xuyu, Yijing Su, Christopher D. Adam, Andre U. Deutschmann, Sarshan R. Pather, Ethan M. Goldberg, Kenong Su, et al. "Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation." Cell Stem Cell 26, no. 5 (May 2020): 766–81. http://dx.doi.org/10.1016/j.stem.2020.02.002.

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Kan, Ryan, Weihong Ge, Can Yilgor, Nicholas Bayley, Christopher Tse, Andrew Tum, Kunal Patel, David Nathanson, and Aparna Bhaduri. "CSIG-15. PTN-PTPRZ1 SIGNALING MEDIATES TUMOR-NORMAL CROSSTALK IN GLIOBLASTOMA." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v43. http://dx.doi.org/10.1093/neuonc/noad179.0171.

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Abstract Glioblastoma (GBM) is the most devastating form of brain cancer with poor patient prognosis and high recurrence. An increasing body of literature suggests crosstalk between tumor and its surroundings, both molding the immune microenvironment and forming functional synapses with neighboring normal cells. Despite the high intra-tumoral and inter-patient heterogeneity, we have discovered PTN-PTPRZ1 signaling as the most significant and preserved communication pathway between GBM cells and their immediate neighboring cells. Through a novel tumor transplantation protocol onto cortical organoids, which are human embryonic stem cell-derived aggregates that faithfully mimic the human brain, we have seen evidence of tumor-normal crosstalk where PTN-PTPRZ1 is a key signaling axis. We hypothesize that PTN-PTPRZ1 signaling is pivotal to tumor growth and invasion, which ultimately leads to recurrence. Modulating PTN and/or PTPRZ1 levels on the cortical organoids via shRNA affects PTN and/or PTPRZ1 expression on the tumors, suggesting dynamic communication between tumor and normal cells via PTN-PTPRZ1 signaling. During the process of generating PTN knockdown cortical organoids, we have additionally discovered a pivotal role for PTN in the very early stages of cortical development. PTN and PTPRZ1 are signature markers of the outer radial glia in the developing human brain, which are absent in mouse models where the majority of PTN biology has been studied. By supplementing exogenous PTN to PTN knockdown organoids and withdrawing it at various timepoints, we have identified drastic phenotypes of neuron and radial glia survival and cell fate specification. With cortical organoids, we can interrogate the role of PTN in the early stages of neurodevelopment via a human-derived system.

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Xiang, Yangfei, Yoshiaki Tanaka, Bilal Cakir, Benjamin Patterson, Kun-Yong Kim, Pingnan Sun, Young-Jin Kang, et al. "hESC-Derived Thalamic Organoids Form Reciprocal Projections When Fused with Cortical Organoids." Cell Stem Cell 24, no. 3 (March 2019): 487–97. http://dx.doi.org/10.1016/j.stem.2018.12.015.

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Santos, Alexandra C., George Nader, Dana El Soufi El Sabbagh, Karolina Urban, Liliana Attisano, and Peter L. Carlen. "Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation." Cells 12, no. 15 (July 27, 2023): 1949. http://dx.doi.org/10.3390/cells12151949.

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Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines for neurological disease. Epilepsy is a complex neurological condition characterized by recurrent seizures. A third of people with epilepsy do not respond to currently available pharmaceutical drugs, and there is not one drug that treats all subtypes; thus, better models of epilepsy are needed for drug development. Cerebral organoids may be used to address this unmet need. In the present work, human cerebral organoids are used along with electrophysiological methods to explore oxygen-glucose deprivation as a hyperexcitability agent. This activity is investigated in its response to current antiseizure drugs. Furthermore, the mechanism of action of the drug candidates is probed with qPCR and immunofluorescence. The findings demonstrate OGD-induced hyperexcitable changes in the cerebral organoid tissue, which is treated with cannabidiol and bumetanide. There is evidence for NKCC1 and KCC2 gene expression, as well as other genes and proteins involved in the complex development of GABAergic signaling. This study supports the use of organoids as a platform for modelling cerebral cortical hyperexcitability that could be extended to modelling epilepsy and used for drug discovery.

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Ben-Yishay, Rakefet Ruth, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, and Dana Ishay-Ronen. "Abstract 5847: Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5847. http://dx.doi.org/10.1158/1538-7445.am2022-5847.

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Abstract Background: Epithelial-mesenchymal transition (EMT) in breast cancer drives tumor invasion, metastasis and drug resistance. BRCA1 mutation carriers have a high risk for developing aggressive basal-like triple-negative breast cancers with EMT characteristics. It has been described that normal mammary epithelium of BRCA1-mutation carriers is comprised of aberrant luminal progenitor cell population resembling basal-like breast cancer cells. Yet, the role of BRCA1 in regulating epithelial cell plasticity in normal mammary gland remains largely obscure. Aim: Here, we used patient-derived normal and cancer organoid cultures from BRCA1-mutation carriers and noncarriers, to examine the effect of the BRCA1 mutation background on epithelial cell plasticity and the susceptibility to EMT. Methods and results: Mammary organoids were established from normal or cancer mammary tissues obtained from consenting patients undergoing lumpectomy or mastectomy. Isolated cells were plated in adherent basement membrane extract (BME) drops and overlaid with optimized organoid culture medium. EMT regulation in breast cancer is usually studied using cell lines and murine models. To determine the possibility to study EMT on patient-derived organoids, organoid culture media was optimized and established organoids were exposed to TGFβ to induce EMT. Morphological and phenotypic alterations were characterized using immunolabeling and visualization with confocal microscopy. Breast cancer organoids induced with TGFβ demonstrated EMT-like changes including the downregulation of E-Cadherin and upregulation of N-Cadherin. Moreover, breast cancer organoids showed typical cytoskeleton rearrangements. Here, the transformation from cortical actin into stress fibers formed in dedifferentiated mesenchymal cells, was visualized with actin staining. However, normal mammary organoids behaved differently. The cytoskeleton of BRCA-wild type (noncarriers) normal mammary organoids was not affected by the treatment. Curiously, normal mammary organoids derived from BRCA1-mutation carriers demonstrated EMT like changes upon exposure to TGFβ. To further determine mechanisms facilitating cell plasticity in BRCA1-mutation carriers, single cell RNA sequencing analysis on BRACA1-mutation carriers and noncarriers derived organoids is ongoing. Conclusion: The results suggest that BRCA1 germline mutation predisposes normal mammary epithelium dedifferentiation due to increased susceptibility to EMT. Citation Format: Rakefet Ruth Ben-Yishay, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, Dana Ishay-Ronen. Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5847.

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Atamian, Alexander, Marcella Birtele, and Giorgia Quadrato. "Not all cortical organoids are created equal." Nature Cell Biology 24, no. 6 (June 2022): 805–6. http://dx.doi.org/10.1038/s41556-022-00890-3.

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Amiri, Anahita, Gianfilippo Coppola, Soraya Scuderi, Feinan Wu, Tanmoy Roychowdhury, Fuchen Liu, Sirisha Pochareddy, et al. "Transcriptome and epigenome landscape of human cortical development modeled in organoids." Science 362, no. 6420 (December 13, 2018): eaat6720. http://dx.doi.org/10.1126/science.aat6720.

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Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.

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Shnaider, T. A. "Cerebral organoids: a promising model in cellular technologies." Vavilov Journal of Genetics and Breeding 22, no. 2 (April 8, 2018): 168–78. http://dx.doi.org/10.18699/vj18.344.

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The development of the human brain is a complex multi-stage process including the formation of various types of neural cells and their interactions. Many fundamental mechanisms of neurogenesis have been established due to the studying of model animals. However, significant differences in the brain structure compared to other animals do not allow considering all aspects of the human brain formation, which could play the main role in the development of unique cognitive abilities for human. Four years ago, Lancaster’s group elaborated human pluripotent stem cell-derived three-dimensional cerebral organoid technology, which opened a unique opportunity for researchers to model early stages of human neurogenesis in vitro. Cerebral organoids closely remodel many endogenous brain regions with specific cell composition like ventricular zone with radial glia, choroid plexus, and cortical plate with upper and deeper-layer neurons. Moreover, human brain development includes interactions between different brain regions. Generation of hybrid three-dimensional cerebral organoids with different brain region identity allows remodeling some of them, including long-distance neuronal migration or formation of major axonal tracts. In this review, we consider the technology of obtaining human pluripotent stem cell-derived three-dimensional cerebral organoids with different modifications and with different brain region identity. In addition, we discuss successful implementation of this technology in fundamental and applied research like modeling of different neurodevelopmental disorders and drug screening. Finally, we regard existing problems and prospects for development of human pluripotent stem cell-derived threedimensional cerebral organoid technology.

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López-Tobón, Alejandro, Carlo Emanuele Villa, Cristina Cheroni, Sebastiano Trattaro, Nicolò Caporale, Paola Conforti, Raffaele Iennaco, et al. "Human Cortical Organoids Expose a Differential Function of GSK3 on Cortical Neurogenesis." Stem Cell Reports 13, no. 5 (November 2019): 847–61. http://dx.doi.org/10.1016/j.stemcr.2019.09.005.

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Hernández, Damián, Duncan E. Crombie, Helena H. Liang, Lisa Kearns, Sze W. Ng, Elizabeth de Smit, Linda Clarke, et al. "MODELLING ALZHEIMER’S DISEASE USING HUMAN CORTICAL CEREBRAL ORGANOIDS." Alzheimer's & Dementia 13, no. 7 (July 2017): P1482—P1483. http://dx.doi.org/10.1016/j.jalz.2017.07.559.

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Pérez-Brangulí, Francesc, Isabel Y. Buchsbaum, Tatyana Pozner, Martin Regensburger, Wenqiang Fan, Annika Schray, Tom Börstler, et al. "Human SPG11 cerebral organoids reveal cortical neurogenesis impairment." Human Molecular Genetics 28, no. 6 (November 22, 2018): 961–71. http://dx.doi.org/10.1093/hmg/ddy397.

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Prior, Victoria, Simon Maksour, Sara Miellet, Amy Hulme, Mehdi Mirzaei, Yunqi Wu, Mirella Dottori, and Geraldine O’Neill. "BIOL-09. PROTEOMIC ANALYSES REVEAL THAT CO-CULTURE OF DIFFUSE INTRINSIC PONTINE GLIOME (DIPG) WITH CORTICAL ORGANOIDS ALTERS CELL ADHESION, DNA SYNTHESIS AND REPLICATION, AND DENDRITIC GROWTH SIGNALLING." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i7. http://dx.doi.org/10.1093/neuonc/noad073.028.

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Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly brain cancers in children for which there is currently no effective treatment. In part, this can be attributed to preclinical models that lack essential elements of the in vivo tissue environment, resulting in treatments that appear promising preclinically, but fail to result in effective cures. Recently developed co-culture models combining stem cell-derived brain organoids with brain cancer cells provide tissue dimensionality and a human-relevant tissue-like microenvironment. As these models are technically challenging and time consuming it is imperative to establish whether interaction with the organoid influences DIPG biology and thus warrants their use. To address this question, we cultured DIPG cells with GFP-expressing cortical organoids. We created “mosaic” co-cultures enriched for tumour cell-neuronal cell interactions, where disaggregated spheroids and organoids were mixed and allowed to reform, versus “assembloid” co-cultures enriched for tumour cell-tumour cell interactions, where preformed tumour spheroids and organoids were combined. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) was used to analyse the proteomes of DIPG fractions isolated by flow-assisted cell sorting. Control proteomes from DIPG spheroids were compared with DIPG cells isolated from mosaic and assembloid co-cultures. This revealed that tumour cell adhesion was reduced, and DNA synthesis and replication were increased, in DIPG cells under either co-culture condition. By contrast, the mosaic co-culture was alone associated with pathways implicated in dendrite growth. We propose that co-culture with brain organoids is a valuable tool to parse the contribution of the brain microenvironment to DIPG tumour biology.

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Yi, Sang Ah, Ki Hong Nam, Jihye Yun, Dongmin Gim, Daeho Joe, Yong Ho Kim, Han-Joo Kim, Jeung-Whan Han, and Jaecheol Lee. "Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus." Viruses 12, no. 9 (September 8, 2020): 1004. http://dx.doi.org/10.3390/v12091004.

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Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.

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Ma, Haihua, Juan Chen, Zhiyu Deng, Tingting Sun, Qingming Luo, Hui Gong, Xiangning Li, and Ben Long. "Multiscale Analysis of Cellular Composition and Morphology in Intact Cerebral Organoids." Biology 11, no. 9 (August 26, 2022): 1270. http://dx.doi.org/10.3390/biology11091270.

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Cerebral organoids recapitulate in vivo phenotypes and physiological functions of the brain and have great potential in studying brain development, modeling diseases, and conducting neural network research. It is essential to obtain whole-mount three-dimensional (3D) images of cerebral organoids at cellular levels to explore their characteristics and applications. Existing histological strategies sacrifice inherent spatial characteristics of organoids, and the strategy for volume imaging and 3D analysis of entire organoids is urgently needed. Here, we proposed a high-resolution imaging pipeline based on fluorescent labeling by viral transduction and 3D immunostaining with fluorescence micro-optical sectioning tomography (fMOST). We were able to image intact organoids using our pipeline, revealing cytoarchitecture information of organoids and the spatial localization of neurons and glial fibrillary acidic protein positive cells (GFAP+ cells). We performed single-cell reconstruction to analyze the morphology of neurons and GFAP+ cells. Localization and quantitative analysis of cortical layer markers revealed heterogeneity of organoids. This pipeline enabled acquisition of high-resolution spatial information of millimeter-scale organoids for analyzing their cell composition and morphology.

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Cho, Ann-Na, Fiona Bright, Nicolle Morey, Carol Au, Lars M. Ittner, and Yazi D. Ke. "Efficient Gene Expression in Human Stem Cell Derived-Cortical Organoids Using Adeno Associated Virus." Cells 11, no. 20 (October 11, 2022): 3194. http://dx.doi.org/10.3390/cells11203194.

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Cortical organoids are 3D structures derived either from human embryonic stem cells or human induced pluripotent stem cells with their use exploding in recent years due to their ability to better recapitulate the human brain in vivo in respect to organization; differentiation; and polarity. Adeno-associated viruses (AAVs) have emerged in recent years as the vectors of choice for CNS-targeted gene therapy. Here; we compare the use of AAVs as a mode of gene expression in cortical organoids; over traditional methods such as lipofectamine and electroporation and demonstrate its ease-of-use in generating quick disease models through expression of different variants of the central gene—TDP-43—implicated in amyotrophic lateral sclerosis and frontotemporal dementia.

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Hale, Andrew T., Yuwei Song, and Zechen Chong. "268 Integrative Genomics Identifies Evolutionary, Temporal, and Cell-lineage Origin of Hydrocephalus Risk Gene." Neurosurgery 70, Supplement_1 (April 2024): 75. http://dx.doi.org/10.1227/neu.0000000000002809_268.

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INTRODUCTION: Our previous work identified MAEL, a gene involved in regulation of DNA transposon activity and histone methylation, as a transcriptome-wide predictor of pediatric hydrocephalus (Hale et al., Cell Reports, 2021). Here we aim to characterize the function of MAEL across timescales and cell-lineages in the developing human brain to understand the pathophysiological basis of hydrocephalus. METHODS: We performed taxonomic analysis of MAEL across species using Ensemble. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across the prenatal period from the Developing Human Brain Atlas (Allen Institute) and an atlas of late-prenatal cortical tissue identified temporospatial MAEL expression patterns. Finally, to estimate the degree to which in vitro models recapitulate expression patterns of MAEL in the developing brain, we analyzed scRNA-seq from human neural and choroid-plexus organoids. RESULTS: We performed taxonomic evolutionary gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in model systems. MAEL is among the top 0.01% human-specific genes and shares < 50% sequence homology with mammalian model organisms. scRNA-seq identified MAEL first detected in the telencephalon at 9 weeks post-conception, highest expressed in the sub-ventricular zone at 16 weeks, and lowest expressed in the hippocampus at 21 weeks post conception. Temporospatial expression of MAEL in the late-prenatal cortex identifies MAEL expression largely restricted to the neural progenitor cells before reaching steady-state expression throughout the cortical layers at 39 weeks gestation. Finally, spatial MAEL expression is largely preserved in brain organoids and robustly expressed in choroid plexus organoids highlighting the utility of these models in future mechanistic studies. CONCLUSIONS: We delineate the evolutionary origin and temporospatial patterns of MAEL expression in the developing human brain and organoid models. These data provide the premise for understanding the detailed molecular-genetic underpinnings of hydrocephalus.

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Bhaduri, Aparna, Madeline G. Andrews, Walter Mancia Leon, Diane Jung, David Shin, Denise Allen, Dana Jung, et al. "Cell stress in cortical organoids impairs molecular subtype specification." Nature 578, no. 7793 (January 29, 2020): 142–48. http://dx.doi.org/10.1038/s41586-020-1962-0.

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Schukking, Monique, Helen C. Miranda, Cleber A. Trujillo, Priscilla D. Negraes, and Alysson R. Muotri. "Direct Generation of Human Cortical Organoids from Primary Cells." Stem Cells and Development 27, no. 22 (November 15, 2018): 1549–56. http://dx.doi.org/10.1089/scd.2018.0112.

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Muotri, Alysson. "Emergence of nested oscillatory dynamics in human cortical organoids." IBRO Reports 6 (September 2019): S25. http://dx.doi.org/10.1016/j.ibror.2019.07.067.

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Hali, Sai, Jonghun Kim, Tae Hwan Kwak, Hyunseong Lee, Chan Young Shin, and Dong Wook Han. "Modelling monogenic autism spectrum disorder using mouse cortical organoids." Biochemical and Biophysical Research Communications 521, no. 1 (January 2020): 164–71. http://dx.doi.org/10.1016/j.bbrc.2019.10.097.

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Nowakowski, Tomasz J., and Sofie R. Salama. "Cerebral Organoids as an Experimental Platform for Human Neurogenomics." Cells 11, no. 18 (September 8, 2022): 2803. http://dx.doi.org/10.3390/cells11182803.

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The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate expansion of the prefrontal cortex in humans. Yet our mechanistic understanding of neurodevelopmental processes is derived overwhelmingly from rodent models, which fail to capture many human-enriched features of cortical development. With the advent of pluripotent stem cells and technologies for differentiating three-dimensional cultures of neural tissue in vitro, cerebral organoids have emerged as an experimental platform that recapitulates several hallmarks of human brain development. In this review, we discuss the merits and limitations of cerebral organoids as experimental models of the developing human brain. We highlight innovations in technology development that seek to increase its fidelity to brain development in vivo and discuss recent efforts to use cerebral organoids to study regeneration and brain evolution as well as to develop neurological and neuropsychiatric disease models.

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Kim, Bumsoo, Yongjun Koh, Hyunsu Do, Younghee Ju, Jong Bin Choi, Gahyang Cho, Han-Wook Yoo, et al. "Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs." International Journal of Molecular Sciences 23, no. 22 (November 10, 2022): 13861. http://dx.doi.org/10.3390/ijms232213861.

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Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations in Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Although diverse neurological manifestations are commonly diagnosed in NS patients, the mechanisms as to how SHP2 mutations induce the neurodevelopmental defects associated with NS remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs develop normally in their appearance, single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS.

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Pranty, Abida Islam, Wasco Wruck, and James Adjaye. "Free Bilirubin Induces Neuro-Inflammation in an Induced Pluripotent Stem Cell-Derived Cortical Organoid Model of Crigler-Najjar Syndrome." Cells 12, no. 18 (September 14, 2023): 2277. http://dx.doi.org/10.3390/cells12182277.

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Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus enabling albumin-unbound free bilirubin (BF) to cross the blood–brain barrier and accumulate within. A defect in the UGT1A1 enzyme-encoding gene, which is directly responsible for bilirubin conjugation, can cause Crigler–Najjar syndrome (CNS) and Gilbert’s syndrome. We used human-induced pluripotent stem cell (hiPSC)-derived 3D brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of BF in the developing human brain. Healthy and patient-derived iPSCs were differentiated into day-20 brain organoids, and then stimulated with 200 nM BF. Analyses at 24 and 72 h post-treatment point to BF-induced neuro-inflammation in both cell lines. Transcriptome, associated KEGG, and Gene Ontology analyses unveiled the activation of distinct inflammatory pathways, such as cytokine–cytokine receptor interaction, MAPK signaling, and NFκB activation. Furthermore, the mRNA expression and secretome analysis confirmed an upregulation of pro-inflammatory cytokines such as IL-6 and IL-8 upon BF stimulation. This novel study has provided insights into how a human iPSC-derived 3D brain organoid model can serve as a prospective platform for studying the etiology of BIND kernicterus.

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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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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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Denoth-Lippuner, Annina, Lars N. Royall, Daniel Gonzalez-Bohorquez, Diana Machado, and Sebastian Jessberger. "Injection and electroporation of plasmid DNA into human cortical organoids." STAR Protocols 3, no. 1 (March 2022): 101129. http://dx.doi.org/10.1016/j.xpro.2022.101129.

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McMahon, Courtney L., Hilary Staples, Michal Gazi, Ricardo Carrion, and Jenny Hsieh. "SARS-CoV-2 targets glial cells in human cortical organoids." Stem Cell Reports 16, no. 5 (May 2021): 1156–64. http://dx.doi.org/10.1016/j.stemcr.2021.01.016.

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Hou, Zongkun, Shilei Hao, and Bochu Wang. "The Mechanical Mechanism of Cortical Folding on 3D Cerebral Organoids." Molecular & Cellular Biomechanics 16, S2 (2019): 145. http://dx.doi.org/10.32604/mcb.2019.07077.

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Yao, Hang, Wei Wu, Ines Cerf, Helen W. Zhao, Juan Wang, Priscilla D. Negraes, Alysson R. Muotri, and Gabriel G. Haddad. "Methadone interrupts neural growth and function in human cortical organoids." Stem Cell Research 49 (December 2020): 102065. http://dx.doi.org/10.1016/j.scr.2020.102065.

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Li, Xiao-Hong, Di Guo, Li-Qun Chen, Zhe-Han Chang, Jian-Xin Shi, Nan Hu, Chong Chen, et al. "Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits." Brain, May 13, 2024. http://dx.doi.org/10.1093/brain/awae150.

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Abstract Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.

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Wilson, Madison N., Martin Thunemann, Xin Liu, Yichen Lu, Francesca Puppo, Jason W. Adams, Jeong-Hoon Kim, et al. "Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex." Nature Communications 13, no. 1 (December 26, 2022). http://dx.doi.org/10.1038/s41467-022-35536-3.

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AbstractHuman cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.

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Cadena, Melissa A., Anson Sing, Kylie Taylor, Linqi Jin, Liqun Ning, Mehdi Salar Amoli, Yamini Singh, et al. "A 3D Bioprinted Cortical Organoid Platform for Modeling Human Brain Development." Advanced Healthcare Materials, May 30, 2024. http://dx.doi.org/10.1002/adhm.202401603.

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AbstractThe ability to promote three‐dimensional (3D) self‐organization of induced pluripotent stem cells into complex tissue structures called organoids presents new opportunities for the field of developmental biology. Brain organoids have been used to investigate principles of neurodevelopment and neuropsychiatric disorders and serve as a drug screening and discovery platform. However, brain organoid cultures are currently limited by a lacking ability to precisely control their extracellular environment. Here, we employed 3D bioprinting to generate a high‐throughput, tunable, and reproducible scaffold for controlling organoid development and patterning. Additionally, our approach supports the co‐culture of organoids and vascular cells in a custom architecture containing interconnected endothelialized channels. Printing fidelity and mechanical assessments confirm that fabricated scaffolds closely match intended design features and exhibit stiffness values reflective of the developing human brain. Using organoid growth, viability, cytoarchitecture, proliferation, and transcriptomic benchmarks, we found that organoids cultured within the bioprinted scaffold long‐term are healthy and have expected neuroectodermal differentiation. Lastly, we confirmed that the endothelial cells in printed channel structures can migrate towards and infiltrate into the embedded organoids. This work demonstrates a tunable 3D culturing platform that can be used to create more complex and accurate models of human brain development and underlying diseases.This article is protected by copyright. All rights reserved

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Zourray, Clara, Manju A. Kurian, Serena Barral, and Gabriele Lignani. "Electrophysiological Properties of Human Cortical Organoids: Current State of the Art and Future Directions." Frontiers in Molecular Neuroscience 15 (February 16, 2022). http://dx.doi.org/10.3389/fnmol.2022.839366.

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Human cortical development is an intricate process resulting in the generation of many interacting cell types and long-range connections to and from other brain regions. Human stem cell-derived cortical organoids are now becoming widely used to model human cortical development both in physiological and pathological conditions, as they offer the advantage of recapitulating human-specific aspects of corticogenesis that were previously inaccessible. Understanding the electrophysiological properties and functional maturation of neurons derived from human cortical organoids is key to ensure their physiological and pathological relevance. Here we review existing data on the electrophysiological properties of neurons in human cortical organoids, as well as recent advances in the complexity of cortical organoid modeling that have led to improvements in functional maturation at single neuron and neuronal network levels. Eventually, a more comprehensive and standardized electrophysiological characterization of these models will allow to better understand human neurophysiology, model diseases and test novel treatments.

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Journal articles on the topic 'Cortical organoids'

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