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Remodeling and repair of the damaged brain: the potential and challenges of organoids for ischaemic stroke.
Ischemic stroke induces irreversible cerebral tissue damage, a condition exacerbated by the brain's limited endogenous neuroplasticity and inability to regenerate neurons. While neural circuit reorganization holds therapeutic potential, its efficacy is hindered by pathological barriers such as glial scarring, chronic inflammation, and neurotrophic factor deficiency. Although pharmacological and interventional methods for stroke have been well developed, their functional recovery outcomes remain suboptimal. Emerging neural regeneration paradigms, particularly stem cell-based strategies (encompassing neural stem cell transplantation, neural progenitors grafts, and 3D brain organoid implantation), offer novel solutions to these challenges. However, critical limitations persist in conventional stem cell approaches: (1) compromised synaptic integration efficacy hinders functional neural circuit reconstruction; (2) the absence of functional vascular niches coupled with deficient astrocyte-mediated support and extracellular matrix signaling; (3) restricted regenerative capacity despite theoretical multipotent differentiation potential. Recent breakthroughs in cerebral organoid technology have revolutionized neurological disease modeling and neural repair research. Building upon this paradigm shift, our study mechanistically interrogates neuroplastic remodeling processes following ischemic stroke, while critically evaluating the therapeutic efficacy and inherent limitations of stem cell-based interventions. This affirms the critical role of 3D human cerebral organoid transplantation in the reconstruction of neural circuits. Additionally, we further summarize the utility of organoid-based disease models and address associated ethical and societal concerns. Future efforts should prioritize the clinical translation of organoid transplantation for ischemic stroke, aiming to mitigate neurological deficits and restore functional recovery.
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Mechanics of human brain organoids.
Organoids are prototypes of human organs derived from cultured human stem cells. They provide a reliable and accurate experimental model to study the physical mechanisms underlying the early developmental stages of human organs and, in particular, the early morphogenesis of the cortex. Here we propose a mathematical model to elucidate the role played by two mechanisms which have been experimentally proven to be crucial in shaping human brain organoids: the contraction of the inner core of the organoid and the microstructural remodeling of its outer cortex. Our results show that both mechanisms are crucial for the final shape of the organoid and that perturbing those mechanisms can lead to pathological morphologies which are reminiscent of those associated with lissencephaly (smooth brain).
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Method to Generate Dorsal Forebrain Brain Organoids from Human Pluripotent Stem Cells.
Region-specific brain organoids, such as dorsal forebrain brain organoid, have become increasingly useful to model early brain development. Importantly, these organoids provide an avenue to investigate mechanisms underlying neurodevelopmental disorders, as they undergo developmental milestones resembling early neocortical formation. These milestones include the generation of neural precursors which transition into intermediate cell types and subsequently to neurons and astrocytes, as well as the fulfillment of key neuronal maturation events such as synapse formation and pruning. Here we describe how to generate free-floating dorsal forebrain brain organoids from human pluripotent stem cells (hPSCs). We also describe validation of the organoids via cryosectioning and immunostaining. Additionally, we include an optimized protocol that allows high-quality dissociation of the brain organoids to live single cells, a critical step for downstream single-cell assays.
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Brain organoids, high-density MEAs, and deep learning: A new paradigm for functional neurobiomarker discovery.
Biomarker discovery, essential in neuroscience research, has traditionally been based on static molecular omics, which frequently reveal established pathogenesis at the network level when irreversible structural damage occurs. In this review, the paradigm shift of functional "digital phenotyping" is discussed, along with its implementation by combining human induced pluripotent stem cell (hiPSC)-derived brain organoids with high-density multielectrode arrays (HD-MEAs). Researchers can use advanced architecture deep learning (DL) algorithms, such as Convolutional and Graph Neural Networks, to identify predictive signatures of diseases at the network level by separating complex spatiotemporal dynamics in firing patterns. These digital functional biomarkers can their ability to detect abnormal burst kinetics, abnormal oscillatory coupling, and abnormal functional connectomes before the onset of structural cell loss. Moreover, we discuss the underlying methods of artificial intelligence (AI) analysis and advances in phenotypic drug discovery using organoid electrophysiology, changing the paradigm of therapeutic targeting from the clearance of molecular aggregates to the functional recuperation of neural circuit health. In conclusion, a combination of powerful 3D culture technology, state-of-the-art microelectronics, and machine learning offers an extensive novel translational platform for dissecting early neurodevelopmental and neurodegenerative diseases, ultimately driving precision therapeutic approaches for the brain and other organs.
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Clonidine prevents radiation-induced cell death in human brain organoids.
Radiotherapy is a standard treatment of pediatric brain tumors. Though the survival rate has improved for many tumor types, most patients suffer long-term cognitive decline and there is currently no way of preventing radiation-induced damage to healthy brain tissue. Here, we used a human forebrain organoid model to investigate if the α2-adrenoceptor and I1-imidazoline receptor agonist clonidine could prevent radiotoxicity. We found that treatment of organoids with clonidine significantly reduced radiation-induced loss of neural progenitor cells, neurons, astrocytes, and oligodendrocyte lineage cells. Moreover, clonidine reduced overall DNA damage and signs of reactive gliosis in organoids. Our findings demonstrate that pharmacological rescue of radiation neurotoxicity is possible in a human brain organoid model and provides a rationale for future drug repurposing studies aiming to prevent radiation-induced brain injury in children treated with radiotherapy.
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One-Step Drug Screening System Utilizing Electrophysiological Activity in Multiple Brain Organoids.
Human-induced pluripotent stem cell (iPSC)-derived brain organoids have attracted significant attention as promising models for drug screening owing to their remarkable resemblance to the human brain. The advent of disease model organoids, derived from patient's cells, has further elevated expectations for drug screening and personalized medicine. Nevertheless, the absence of a comprehensive platform for administering drugs and assessing their efficacy based on functional changes in brain organoids has remained a challenge. In this study, we introduce a one-step drug screening system designed designed to investigate functional changes induced by diverse drug doses in multiple brain organoids, utilizing electrophysiological signal measurements. Our system comprises a specialized culture chamber with a microfluidic chip capable of accommodating 10 organoids and delivering varying doses of two drugs to each organoid. Additionally, we integrate a three dimentional microelectrode array (3D MEA) with ten shanks, enabling functional assessment of 10 brain organoids. This approach facilitates dose-dependent drug screening across multiple organoids. We demonstrate the effectiveness of our system through real-time analysis of neural activity changes triggered by different doses of pottassium chloride (KCl). Furthermore, sodium channel protein type 2 subunit alpha (SCN2A)-epileptic organoids to demonstrate utility in disease-model-based drug screening. Our platform enables functional screening and personalized medicine using brain organoids.
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Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras.
Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contributes to a balanced approach for proceeding with studies involving brain organoid transplantation and other forms of human-animal brain chimeras.
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Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.
A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.
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Brain organoids in Alzheimer disease and related tauopathies: Challenges and opportunities for translational readiness.
A major hurdle in Alzheimer disease research is the failure of mouse models to capture complexities of the human brain that contributes to repeated clinical trial failure. Although the recent US Food and Drug Administration (FDA) Modernization Act 2.0 has enabled non-animal preclinical pathways, brain organoid models of tauopathies remain nascent compared with other disease areas. Here, we identify three challenges for their translational readiness, maturity, disease-relevant cellular complexity, and pathological accuracy, and examine current achievements and emerging solutions. We propose a ten-metric benchmarking framework and discuss the opportunities and remaining challenges for translational readiness in tauopathy modeling.
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Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.
Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.