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KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury.
Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.
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MeCP2 dysfunction prevents proper BMP signaling and neural progenitor expansion in brain organoid.
OBJECTIVES: Sporadic mutations in MeCP2 are a hallmark of Rett syndrome (RTT). Many RTT brain organoid models have exhibited pathogenic phenotypes such as decreased spine density and small size of soma with altered electrophysiological signals. However, previous models are mainly focused on the phenotypes observed in the late phase and rarely provide clues for the defect of neural progenitors which generate different types of neurons and glial cells. METHODS: We newly established the RTT brain organoid model derived from MeCP2-truncated iPS cells which were genetically engineered by CRISPR/Cas9 technology. By immunofluorescence imaging, we studied the development of NPC pool and its fate specification into glutamatergic neurons or astrocytes in RTT organoids. By total RNA sequencing, we investigated which signaling pathways were altered during the early brain development in RTT organoids. RESULTS: Dysfunction of MeCP2 caused the defect of neural rosette formation in the early phase of cortical development. In total transcriptome analysis, BMP pathway-related genes are highly associated with MeCP2 depletion. Moreover, levels of pSMAD1/5 and BMP target genes are excessively increased, and treatment of BMP inhibitors partially rescues the cell cycle progression of neural progenitors. Subsequently, MeCP2 dysfunction reduced the glutamatergic neurogenesis and induced overproduction of astrocytes. Nevertheless, early inhibition of BMP pathway rescued VGLUT1 expression and suppressed astrocyte maturation. INTERPRETATION: Our results demonstrate that MeCP2 is required for the expansion of neural progenitor cells by modulating BMP pathway at early stages of development, and this influence persists during neurogenesis and gliogenesis at later stages of brain organoid development.
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Modelling Brain Metastasis: Standardized Analysis of Metastatic Colonization and Histological Growth Patterns by Stereotactic Intracortical Injection.
Brain metastases are a common and devastating complication of advanced solid tumors, frequently associated with poor prognosis, neurological decline, and reduced quality of life. The incidence of central nervous system (CNS) failure and neurological death is rapidly increasing, yet the mechanisms driving the final stages of brain metastasis, such as secondary dissemination, re-colonization, and the contribution of the histological growth pattern (HGP) as a potential surrogate parameter, remain poorly understood. The standardized stereotactic intracortical injection model enables precise and reproducible implantation of tumor cells, or mixed populations including stromal or immune components, directly into the mouse cerebral cortex. This protocol also supports the creation of a preclinical tissue archive, offering a robust platform for investigating essential aspects of CNS colonization, such as: metastatic outgrowth, HGP-specific growth dynamics, and pathophysiological mechanisms contributing to neurological failure. Additionally, this model supports pharmacological testing in a reproducible clinically relevant context. Unlike systemic injection methods (e.g., tail vein or intracardiac), which are optimized for studying early metastatic steps but result in variable and often low rates of brain colonization, the stereotactic model ensures consistent, brain-specific metastatic growth and enables the investigation of late stages of CNS metastasis. Compared to ex vivo systems such as organoids or brain slice cultures, the in vivo stereotactic model preserves vascularization, systemic signaling, and the full complexity of the brain's immune landscape, supporting long-term studies of tumor progression and therapeutic response. By providing a reproducible and clinically relevant platform, our model advances the field's ability to identify prognostic markers, explore therapeutic strategies, and understand the mechanisms of late-stage brain metastasis.
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Beyond consciousness: Ethical, legal, and social issues in human brain organoid research and application.
This study aims to provide a comprehensive review of the ethical, legal and social issues in human brain organoid research, with a view to different types of research and applications: in vitro research, transplantation into non-human animals, and biocomputing. Despite the academic and societal attention on the possibility that human brain organoids may be conscious, we have identified diverse issues in human brain organoid research and applications. To guide the complex terrain of human brain organoid research and applications, a multidisciplinary approach that integrates ethical, legal, and social perspectives is essential.
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Vascularization and Engraftment of Transplanted Human Cerebral Organoids in Mouse Cortex.
Neural stem cells (NSCs) hold great promise for neural repair in cases of CNS injury and neurodegeneration; however, conventional cell-based transplant methods face the challenges of poor survival and inadequate neuronal differentiation. Here, we report an alternative, tissue-based transplantation strategy whereby cerebral organoids derived from human pluripotent stem cells (PSCs) were grafted into lesioned mouse cortex. Cerebral organoid transplants exhibited enhanced survival and robust vascularization from host brain as compared to transplants of dissociated neural progenitor cells (NPCs). Engrafted cerebral organoids harbored a large NSC pool and displayed multilineage neurodifferentiation at two and four weeks after grafting. Cerebral organoids therefore represent a promising alternative source to NSCs or fetal tissues for transplantation, as they contain a large set of neuroprogenitors and differentiated neurons in a structured organization. Engrafted cerebral organoids may also offer a unique experimental paradigm for modeling human neurodevelopment and CNS diseases in the context of vascularized cortical tissue.
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Stem Cell Models of Human Brain Development.
Recent breakthroughs in pluripotent stem cell technologies have enabled a new class of in vitro systems for functional modeling of human brain development. These advances, in combination with improvements in neural differentiation methods, allow the generation of in vitro systems that reproduce many in vivo features of the brain with remarkable similarity. Here, we describe advances in the development of these methods, focusing on neural rosette and organoid approaches, and compare their relative capabilities and limitations. We also discuss current technical hurdles for recreating the cell-type complexity and spatial architecture of the brain in culture and offer potential solutions.
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Free Bilirubin Induces Neuro-Inflammation in an Induced Pluripotent Stem Cell-Derived Cortical Organoid Model of Crigler-Najjar Syndrome.
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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Are There Islands of Awareness?
Ordinary human experience is embedded in a web of causal relations that link the brain to the body and the wider environment. However, there might be conditions in which brain activity supports consciousness even when that activity is fully causally isolated from the body and its environment. Such cases would involve what we call islands of awareness: conscious states that are neither shaped by sensory input nor able to be expressed by motor output. This Opinion paper considers conditions in which such islands might occur, including ex cranio brains, hemispherotomy, and in cerebral organoids. We examine possible methods for detecting islands of awareness, and consider their implications for ethics and for the nature of consciousness.
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A 3D Microfluidic Device with Vertical Channels toward In Vitro Reconstruction of Blood-Brain Barrier.
This paper reports a three-dimensional microfluidic device with an array of vertical channels to enable regulated, continuous, vertical flows to emulate the environment for in vitro culturing of brain and blood vessel organoids. This is expected to ultimately lead to in vitro reconstruction of the blood-brain barrier that is of high interest to studies on mental illness mechanisms and drug delivery to the brain. Twelve vertical microfluidic channels, each with 300 µm diameter and 5 mm height, were formed in the high-permeability agar gel surrounding the organoid to realize the vertical circulation flows and to allow lateral diffusion flows. The combined vertical flow rate of all channels ranges from 2.1 to 6.8 mL/min under different control parameters. A 30-day-old human blood vessel organoid was planted into the device for initial culturing and flow function tests. The result indicates that the organoid was properly activated with effective flow generation in the culturing site of the device.
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Emerging brain organoids: 3D models to decipher, identify and revolutionize brain.
Brain organoids are an emerging in vitro 3D brain model that is integrated from pluripotent stem cells. This model mimics the human brain's developmental process and disease-related phenotypes to a certain extent while advancing the development of human brain-based biological intelligence. However, many limitations of brain organoid culture (e.g., lacking a functional vascular system, etc.) prevent in vitro-cultured organoids from truly replicating the human brain in terms of cell type and structure. To improve brain organoids' scalability, efficiency, and stability, this paper discusses important contributions of material biology and microprocessing technology in solving the related limitations of brain organoids and applying the latest imaging technology to make real-time imaging of brain organoids possible. In addition, the related applications of brain organoids, especially the development of organoid intelligence combined with artificial intelligence, are analyzed, which will help accelerate the rational design and guidance of brain organoids.