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Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model.
BACKGROUND: HIV-1-associated neurocognitive impairment (HIV-1-NCI) is marked by ongoing and chronic neuroinflammation with loss and decline in neuronal function even when antiretroviral drug therapy (ART) successfully suppresses viral replication. Microglia, the primary reservoirs of HIV-1 in the central nervous system (CNS), play a significant role in maintaining this neuroinflammatory state. However, understanding how chronic neuroinflammation is generated and sustained by HIV-1, or impacted by ART, is difficult due to limited access to human CNS tissue. METHODS: We generated an in vitro model of admixed hematopoietic progenitor cell (HPC) derived microglia embedded into embryonic stem cell (ESC) derived Brain Organoids (BO). Microglia were infected with HIV-1 prior to co-culture. Infected microglia were co-cultured with brain organoids BOs to infiltrate the BOs and establish a model for HIV-1 infection, "HIV-1 M-BO". HIV-1 M-BOs were treated with ART for variable directions. HIV-1 infection was monitored with p24 ELISA and by digital droplet PCR (ddPCR). Inflammation was measured by cytokine or p-NF-kB levels using multiplex ELISA, flow cytometry and confocal microscopy. RESULTS: HIV-1 infected microglia could be co-cultured with BOs to create a model for "brain" HIV-1 infection. Although HIV-1 infected microglia were the initial source of pro-inflammatory cytokines, astrocytes, neurons and neural stem cells also had increased p-NF-kB levels, along with elevated CCL2 levels in the supernatant of HIV-1 M-BOs compared to Uninfected M-BOs. ART suppressed the virus to levels below the limit of detection but did not decrease neuroinflammation. CONCLUSIONS: These findings indicate that HIV-1 infected microglia are pro-inflammatory. Although ART significantly suppressed HIV-1 levels, neuronal inflammation persisted in ART-treated HIV-1 M-BOs. Together, these findings indicate that HIV-1 infection of microglia infiltrated into BOs provides a robust in vitro model to understand the impact of HIV-1 and ART on neuroinflammation.
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Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex.
Human 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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Advances in Cerebral Organoid Systems and their Application in Disease Modeling.
Processes associated with human brain development and function are exceedingly complex, limiting our capacity to investigate disease status and potential treatment strategies in vitro. Recent advancements in human cerebral organoid systems-which replicate early stage neural tube formation, neuroepithelium differentiation, and whole-brain regional differentiation-have allowed researchers to generate more accurate models of brain development and disease. The generation of region-specific cerebral organoids also allows for the direct investigation of the etiology and pathological processes associated with inherited and acquired brain diseases, drug discovery, and drug toxicity. In this review, we provide an overview of various neural differentiation technologies, as well as a critical analysis of their strengths and limitations. We primarily focus on the generation of three-dimensional brain organoid systems and their application in infectious disease modeling, high-throughput compound screening, and neurodevelopmental disease modeling.
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Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids.
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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BOMA, a machine-learning framework for comparative gene expression analysis across brains and organoids.
Our machine-learning framework, brain and organoid manifold alignment (BOMA), first performs a global alignment of developmental gene expression data between brains and organoids. It then applies manifold learning to locally refine the alignment, revealing conserved and specific developmental trajectories across brains and organoids. Using BOMA, we found that human cortical organoids better align with certain brain cortical regions than with other non-cortical regions, implying organoid-preserved developmental gene expression programs specific to brain regions. Additionally, our alignment of non-human primate and human brains reveals highly conserved gene expression around birth. Also, we integrated and analyzed developmental single-cell RNA sequencing (scRNA-seq) data of human brains and organoids, showing conserved and specific cell trajectories and clusters. Further identification of expressed genes of such clusters and enrichment analyses reveal brain- or organoid-specific developmental functions and pathways. Finally, we experimentally validated important specific expressed genes through the use of immunofluorescence. BOMA is open-source available as a web tool for community use.
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Organizers in a dish: Modeling human CNS morphogenesis.
The human brain stands out for the scale of cellular and morphological complexity across anterior-posterior domains. Modeling the entire neuraxis is therefore essential to comprehend human neural development and disease. Brain organoids commonly recapitulate anterior regions due to the propensity of neural progenitors to acquire telencephalic identities and self-organize into cortical layers. In the embryo, posterior brain patterning is orchestrated by organizers, signaling centers positioned at anterior-posterior locations that are rarely induced in vitro. Several strategies have been developed to reproduce organizer signals, employing small molecules and recombinant morphogens, thereby expanding the in vitro repertoire of human neural identities. Despite this, posterior models do not yet reproduce the morphological complexity of their in vivo counterparts. In this review, we discuss how this discrepancy may stem from the inability to recapitulate the spatiotemporal dynamics of organizer activity and how recent technologies can balance guided differentiation and self-organization, enhancing the fidelity of human brain organoid models.
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Exploring organoid and assembloid technologies: a focus on retina and brain.
BACKGROUND: The recent emergence of three-dimensional organoids and their utilization as in vitro disease models confirmed the complexities behind organ-specific functions and unravelled the importance of establishing suitable human models for various applications. Also, in light of persistent challenges associated with their use, researchers have been striving to establish more advanced structures (i.e. assembloids) that can help address the limitations presented in the current organoids. METHODS: In this review, we discuss the distinct organoid types that are available to date, with a special focus on retinal and brain organoids, and highlight their importance in disease modelling. RESULTS: We refer to published research to explore the extent to which retinal and brain organoids can serve as potential alternatives to organ/cell transplants and direct our attention to the topic of photostimulation in retinal organoids. Additionally, we discuss the advantages of incorporating microfluidics and organ-on-a-chip devices for boosting retinal organoid performance. The challenges of organoids leading to the subsequent development of assembloid fusion models are also presented. CONCLUSION: In conclusion, organoid technology has laid the foundation for generating upgraded models that not only better replicate in vivo systems but also allow for a deeper comprehension of disease pathophysiology.
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Engineering mechanobiology through organoids-on-chip: A strategy to boost therapeutics.
The mechanical environment of living cells is as critical as chemical signaling. Mechanical stimuli play a pivotal role in organogenesis and tissue homeostasis. Unbalances in mechanotransduction pathways often lead to diseases, such as cancer, cystic fibrosis, and neurodevelopmental disorders. Despite its inherent relevance, there is a lack of proper mechanoresponsive in vitro study systems. In this context, there is an urge to engineer innovative, robust, dynamic, and reliable organotypic technologies to better connect cellular processes to organ-level function and multi-tissue cross-talk. Mechanically active organoid-on-chip has the potential to surpass this challenge. These systems converge microfabrication, microfluidics, biophysics, and tissue engineering fields to emulate key features of living organisms, hence, reducing costs, time, and animal testing. In this review, we intended to present cutting-edge organ-on-chip platforms that integrate biomechanical stimuli as well as novel multicellular culture, such as organoids. We focused on its application in two main fields: precision medicine and drug development. Moreover, we also discussed the state of the art for the development of an engineered model to assess patient-derived tumor organoid metastatic potential. Finally, we highlighted the current drawbacks and emerging opportunities to match the industry needs. We envision the use of mechanoresponsive organotypic-on-chip microdevices as an indispensable tool for precision medicine, drug development, disease modeling, tissue engineering, and developmental biology.
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Recent advances in nanomaterial-based brain organoid on-a-chip for drug evaluation.
Brain organoids have emerged as promising three-dimensional (3D) models that recapitulate key aspects of human brain development, neural circuit formation, and neurological disorders. However, conventional culture systems face critical limitations, including inadequate vascularization, restricted diffusion of nutrients and oxygen, insufficient neuronal maturation, and poor reproducibility, all of which hinder long-term stability and clinical translation. To address these challenges, organoid-on-a-chip technologies have been developed to provide controlled microenvironments, fluidic dynamics, and enhanced tissue integration; nevertheless, significant barriers remain. In recent years, nanomaterials have been increasingly incorporated into brain organoids and chip-based systems to overcome these limitations. Due to their unique structural, electrical, and biochemical properties, nanomaterials can mimic components of the extracellular matrix, promote cellular organization, enhance electrophysiological maturation, and enable advanced sensing modalities. Their integration with organoid-on-a-chip platforms further facilitates vascularization, supports long-term culture, and contributes to the generation of physiologically relevant neural models. This review provides a comprehensive overview of brain organoid technology, the functional roles of nanomaterials in these systems, and recent advances in nanomaterial-based brain organoid-on-a-chip platforms. Additionally, we summarize how these interdisciplinary approaches enhance the modeling of neurological diseases, improve drug evaluation including organoid-based biohybrid robot on-a-chip, and support the development of personalized medicine. Finally, we discuss persisting limitations and outline future directions toward the realization of intelligent, reproducible, and clinically translatable neural platforms. We hope this review will inspire innovative strategies and accelerate progress at the intersection of nanomaterials, organoid biology, and chip-based technologies, thereby advancing personalized and effective treatments in neuroscience and biomedicine.
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Brain Organoid Generation from Induced Pluripotent Stem Cells in Home-Made Mini Bioreactors.
The iPSC-derived brain organoid is a promising technology for in vitro modeling the pathologies of the nervous system and drug screening. This technology has emerged recently. It is still in its infancy and has some limitations unsolved yet. The current protocols do not allow obtaining organoids to be consistent enough for drug discovery and preclinical studies. The maturation of organoids can take up to a year, pushing the researchers to launch multiple differentiation processes simultaneously. It imposes additional costs for the laboratory in terms of space and equipment. In addition, brain organoids often have a necrotic zone in the center, which suffers from nutrient and oxygen deficiency. Hence, most current protocols use a circulating system for culture medium to improve nutrition. Meanwhile, there are no inexpensive dynamic systems or bioreactors for organoid cultivation. This paper describes a protocol for producing brain organoids in compact and inexpensive home-made mini bioreactors. This protocol allows obtaining high quality organoids in large quantities.