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Impact of brain organoid-derived sEVs on metastatic adaptation and invasion of breast carcinoma cells through a microphysiological system.
Brain metastases are common in triple-negative breast cancer (TNBC), suggesting a complex process of cancer spread. The mechanisms enabling TNBC cell adaptation and proliferation in the brain remain unclear. Small extracellular vesicles (sEVs) play a crucial role in communication between breast carcinoma cells and the brain. However, the lack of relevant models hinders understanding of sEV-mediated communication. The present study assesses the impact of brain organoid-derived sEVs (BO-sEVs) on various behaviours of the MDA-MB-231 cell line, chosen as a representative of TNBC in a 3D microfluidic model. Our results demonstrate that 150-200 nm sEVs expressing CD63, CD9, and CD81 from brain organoid media decrease MDA-MB-231 cell proliferation, enhance their wound-healing capacity, alter their morphology into more mesenchymal mode, and increase their stemness. BO-sEVs led to heightened PD-L1, CD49f, and vimentin levels of expression in MDA-MB-231 cells, suggesting an amplified immunosuppressive, stem-like, and mesenchymal phenotype. Furthermore, these sEVs also induced the expression of neural markers such as GFAP in carcinoma cells. The cytokine antibody profiling array also showed that BO-sEVs enhanced the secretion of MCP-1, IL-6, and IL-8 by MDA-MB-231 cells. Moreover, sEVs significantly enhance the migration and invasion of carcinoma cells toward brain organoids in a 3D organoid-on-a-chip system. Our findings emphasize the potential significance of metastatic site-derived sEVs as pivotal mediators in carcinoma progression and adaptation to the brain microenvironment, thereby unveiling novel therapeutic avenues.
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iPSCs-Derived Platform: A Feasible Tool for Probing the Neurotropism of SARS-CoV-2.
Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a severe public health problem with a high rate of morbidity and mortality. A mounting number of clinical investigations illustrate that COVID-19 patients suffer from neurologic conditions in addition to respiratory symptoms. In a recent article, Yuen and colleagues present the first experimental evidence of SARS-CoV-2 infection in the human central nervous system using induced pluripotent stem cells (iPSCs)-derived platform including human neural progenitor cells, neurospheres, and three-dimensional brain organoids (Yuen, K.Y., and Huang, J.D. et al. (2020) Cell Res. DOI: 10.1038/s41422-020-0390-x).
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The Ethics of Cerebral Organoid Research: Being Conscious of Consciousness.
Recently, the use of three-dimensional neural tissues cultured in vitro and called "cerebral organoids" has advanced recapitulation of neural development and disease modeling studies. Along with such advances, cerebral organoid research, and associated concerns call for the elucidation of two points: (1) how cerebral organoid research is currently progressing and the future directions it is likely to take, especially in functional assessment of organoids, and (2) how we should solve ethical issues of possible consciousness in cerebral organoid research. This paper aims first to explore these two issues, and then to present implications and prospects for future cerebral organoid research.
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The importance of accurate representation of human brain organoid research.
Representations of brain organoids in the media are often negatively or positively exaggerated without appropriate discussion. Here, we examine two topics (the possibility of consciousness and medical applications) and call on scientists, ethicists, and the media to represent brain organoid research and its ethical issues more accurately.
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Blood vessel formation in cerebral organoids formed from human embryonic stem cells.
Current cerebral organoid technology provides excellent in vitro models mimicking the structure and function of the developing human brain, which enables studies on normal and pathological brain; however, further improvements are necessary to overcome the problems of immaturity and dearth of non-parenchymal cells. Vascularization is one of the major challenges for recapitulating processes in the developing human brain. Here, we examined the formation of blood vessel-like structures in cerebral organoids induced by vascular endothelial growth factor (VEGF) in vitro. The results indicated that VEGF enhanced differentiation of vascular endothelial cells (ECs) without reducing neuronal markers in the embryonic bodies (EBs), which then successfully developed into cerebral organoids with open-circle vascular structures expressing an EC marker, CD31, and a tight junction marker, claudin-5, characteristic of the blood-brain barrier (BBB). Further treatment with VEGF and Wnt7a promoted the formation of the outer lining consisting of pericyte-like cells, which surrounded the vascular tubes. RNA sequencing revealed that VEGF upregulated genes associated with tube formation, vasculogenesis, and the BBB; it also changed the expression of genes involved in brain embryogenesis, suggesting a role of VEGF in neuronal development. These results indicate that VEGF treatment can be used to generate vessel-like structures with mature BBB characteristics in cerebral organoids in vitro.
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Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann-Pick disease type C.
Recent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.
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Multi-organoid loop cerebral connectoids exhibit enhanced neuronal network dynamics and sequence-specific entrainment.
Reconstructing networks of neurons in vitro is essential for advancing our understanding of functional mechanisms and disease pathogenesis. However, neuronal culture methods including organoids are limited in network structure complexity required for their functionality and dynamics. In this study, we present modular organoid network tissues - loop connectoids - in which multiple cerebral organoids are connected via axon bundles using microfluidic devices. We compared network activity of three- and four-membered loop cerebral connectoids, two reciprocally connected organoids, and single organoids. We observed a significant trend in larger organoid networks exhibiting more complex activity, showing longer activity periods, more bursts, and richer temporal patterns. Additionally, the activity in connectoids shifts closer to a critical state, a hallmark of efficient information processing in the brain, as more organoids are connected. Pharmacological perturbation reveals prominent excitatory and inhibitory responses, supporting the physiological relevance of the observed dynamics. Furthermore, optogenetic stimulation of organoids in a specific sequence can influence their spontaneous activity propagation pattern within the network. This work represents a foundational step toward constructing more complex and physiologically relevant neural networks in vitro, offering a platform for studying neuronal network function and therapeutic intervention.
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Isolation and Culture of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoid Cells.
The advent of human-induced pluripotent stem cell (iPSC)-derived three-dimensional (3D) cerebral organoids provides unprecedented opportunities of modeling human brains in states of health and disorder. Emerging data supports that cerebral organoids allow for more relevant in vitro systems for studying the human brain system and diseases than the current widely used 2D monolayer cell culture. Thus, the ability to isolate, culture, and maintain human brain cells from cerebral organoids is highly needed, particularly for studies on organoid-derived cell-type-specific signaling and their electrophysiological properties. Here we present a protocol to isolate and culture brain cells from 2-month human iPSC-derived cerebral organoids. The dissociation and plating of cells from organoids takes 3-4 h. The dissociated cells can be maintained in culture for up to at least 3 weeks. Some cells expressed the neuron-specific marker microtubule-associated protein 2 and exhibited spontaneous action potentials.
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Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells.
Research on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Here, we describe a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model for the study of Parkinson's disease. Midbrain organoids are characterized in detail for neuronal, astroglial, and oligodendrocyte differentiation. Furthermore, we show the presence of synaptic connections and electrophysiological activity. The complexity of this model is further highlighted by the myelination of neurites. The present midbrain organoid system has the potential to be used for advanced in vitro disease modeling and therapy development.
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Public Engagement With Brain Organoid Research and Application: Lessons From Genome Editing.