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Advances and Applications of Brain Organoids

NEUROSCIENCE BULLETIN (2023)

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Summary: Brain organoids created from human pluripotent stem cells can integrate with the adult rat visual system after transplantation into large injury cavities, suggesting a translational strategy for restoring function after cortical damage. The study provides structural and functional evidence of the successful integration of human brain organoids with the host visual system through a polysynaptic pathway and reciprocal connectivity. Visual stimulation of the host animals elicits responses in the organoid neurons, including orientation selectivity.

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Depressive patient-derived GABA interneurons reveal abnormal neural activity associated with HTR2C

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Summary: This study generated induced pluripotent stem cells (iPSC) from sMDD patients and differentiated them into GABAergic interneurons (GINs) and ventral forebrain organoids. The sMDD GINs showed altered neuronal morphology, increased neural firing, and weakened calcium signaling propagation. It was found that a decreased expression of serotoninergic receptor 2C (5-HT2C) may be responsible for the neuronal activity deficits in sMDD. Targeting the 5-HT2C receptor restored the neuronal activity deficits in sMDD GINs. This research provides a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.

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Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

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Summary: Previous studies have shown that genetic impact of astrocytes in schizophrenia (SCZ) is unknown. Human induced pluripotent stem cell (hiPSC)-derived astrocytes from SCZ twins exhibit gene expression alterations related to synaptic dysfunction, inflammation, and extracellular matrix components. The transplantation of SCZ astrocytes into the mouse forebrain resulted in gene expression changes in brain cells and behavioral changes in cognitive and olfactory functions. Abnormal extracellular matrix composition in the brain is one of the key characteristics in the etiology of SCZ.

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Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids

Michael Notaras et al.

Summary: This study utilized patient-derived induced pluripotent stem cells to generate 3D cerebral organoids to model neuropathology of Schizophrenia. The results revealed specific alterations in neuronal programming factors, disrupted neurogenesis, and changes in growth factor expression, suggesting that Schizophrenia neuropathology could be encoded on a cell-type-by-cell-type basis. Single-cell sequencing identified the depletion of BRN2 and PTN, which were found to be mechanistic substrates of neurogenesis and cellular survival in Schizophrenia organoids.

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Autism genes converge on asynchronous development of shared neuron classes

Bruna Paulsen et al.

Summary: This study utilized organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities resulting from haploinsufficiency in ASD risk genes SUV420H1, ARID1B, and CHD8. The research found asynchronous development of cortical neuronal lineages and distinct molecular pathways associated with these mutations. The study revealed shared cell-type-specific neurodevelopmental abnormalities across ASD risk genes in a manner influenced by individual genomic context.

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Amplification of human interneuron progenitors promotes brain tumors and neurological defects

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APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

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Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease

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Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease

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Human cerebral organoids establish subcortical projections in the mouse brain after transplantation

Xin Dong et al.

Summary: The study demonstrated the successful transplantation of human cerebral organoids into the mouse brain cortex, with the organoids surviving and extending neural projections over 4.5 mm in length within 1 month. The transplanted organoids generated mature neurons and formed synaptic connections with host neurons, integrating into existing neural circuits and impacting the neural behavior of the mice.

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Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer

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A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids

Jong-Chan Park et al.

Summary: This study reports an efficient drug screening platform integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids. By using 1300 organoids from 11 participants, they built a high-content screening system and tested FDA-approved drugs that can permeate the blood-brain barrier. The study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.

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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

Charles Arber et al.

Summary: Mutations in PSEN1 lead to reduced Notch signaling and altered neurogenesis, causing familial Alzheimer's disease. Expression data from stem cells and neurons support this hypothesis, suggesting that neural stem cell biology is affected in aging and disease.

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Establishment and characterization of meningioma patient-derived organoid

Henry Siu Cheung Chan et al.

Summary: 2D cell culture is widely used in tumor research, but may not fully replicate the in vivo tumor structure. Organoid culture is seen as an alternative platform due to its ability to better model tumors. This study established a protocol for culturing cells from patient meningioma tissue in vitro 3D environment, demonstrating the feasibility and potential of organoid technology for meningioma research.

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Cross-Comparison of Human iPSC Motor Neuron Models of Familial and Sporadic ALS Reveals Early and Convergent Transcriptomic Disease Signatures

Ritchie Ho et al.

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3D Genome of macaque fetal brain reveals evolutionary innovations during primate corticogenesis

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Summary: The study reveals human-specific chromatin structure changes in the brain, which play crucial roles in neural circuit formation and plasticity.

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STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation

Louis T. Dang et al.

Summary: In PMSE cortical organoids, an abnormal increase in neural rosette structures and rapid enlargement were observed in the early stages of development, which was dependent on the Wnt pathway. Additionally, delayed neurogenesis, altered cell composition, and abnormal primary cilia architecture were detected, indicating the crucial role of the mTOR pathway in regulating cortical development. By week 12, PMSE organoids showed recovery in neurogenesis but also exhibited increased outer radial glia, suggesting a potential mechanism for megalencephaly in PMSE involving neural stem cell expansion and altered cellular composition during later gestational stages.

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Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

Kornelia Szebenyi et al.

Summary: This study presented a cerebral organoid slice model derived from human induced pluripotent stem cells that recapitulates mature cortical architecture and displays early molecular pathology of ALS/FTD. Distinct transcriptional, proteostasis, and DNA repair disturbances in astroglia and neurons were revealed using single-cell RNA sequencing and biological assays. The results suggest that patient-specific iPSC-derived cortical organoid slice cultures can provide insights into preclinical ALS/FTD mechanisms and potential therapeutic approaches.

NATURE NEUROSCIENCE (2021)

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A growth-factor-activated lysosomal K+ channel regulates Parkinson's pathology

Jinhong Wie et al.

Summary: This study uncovers a pathway by which extracellular growth factors regulate intracellular organelle function, and establishes a targetable mechanism by which common variants of TMEM175 confer risk for Parkinson's disease. The TMEM175 gene's common variants can increase or decrease the risk of developing Parkinson's disease, affecting neuronal damage and defense capabilities.

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Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

Zezhi Li et al.

Summary: Major depressive disorder (MDD), also known as depression, is a common psychiatric disorder with multifactorial etiology. Treatment options include medication and psychotherapy, with advancements in the development of new antidepressants.

NEUROSCIENCE BULLETIN (2021)

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Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations

Noviana Wulansari et al.

Summary: Loss-of-function mutations of DNAJC6 have been found to cause key pathologic features of Parkinson's disease in human midbrain-like organoids, including mDA neuron degeneration, alpha-synuclein aggregation, increased neuronal firing frequency, and mitochondrial and lysosomal dysfunctions. The defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during mDA neuron development, leading to the generation of vulnerable neurons with pathologic manifestations. These findings provide insights into disease mechanisms and potential therapeutic interventions for DNAJC6-PD.

SCIENCE ADVANCES (2021)

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The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease

Aurelie de Rus Jacquet et al.

Summary: This study focused on the effects of a Parkinson's disease-related mutation on astrocytes and neurons, revealing alterations in extracellular vesicle biogenesis and abnormal accumulation of PD-related proteins. The findings suggest that dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of Parkinson's disease.

ELIFE (2021)

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Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Carlo Brighi et al.

Summary: The study reveals that the requirement for the FMRP protein is to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

CELL DEATH & DISEASE (2021)

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Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease

Cameron S. McAlpine et al.

Summary: Communication within the glial cell ecosystem is essential for neuronal and brain health. This study demonstrates that astrocyte-sourced interleukin-3 programs microglia to ameliorate the pathology of Alzheimer's disease by enhancing their ability to clear aggregates of beta-amyloid and tau, ultimately restricting disease progression and cognitive decline. These findings highlight IL-3 as a key mediator of astrocyte-microglia cross-talk and a potential therapeutic target for Alzheimer's disease.

NATURE (2021)

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A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies

Yunhee Kang et al.

Summary: Utilizing a human forebrain organoid model of fragile X syndrome, Kang et al. uncovered the crucial role of FMRP in human brain development and identified numerous human-specific mRNAs potentially regulated by FMRP.

NATURE NEUROSCIENCE (2021)

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The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

David N. Louis et al.

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Newly established patient-derived organoid model of intracranial meningioma

Shintaro Yamazaki et al.

Summary: This study established 18 organoid models of meningiomas and identified upregulated FOXM1 as a potential treatment target for meningioma. Overexpression of FOXM1 in benign meningiomas increased proliferation, while depletion of FOXM1 in malignant meningiomas decreased proliferation. FOXM1 inhibitor thiostrepton combined with radiation therapy significantly inhibited the proliferation of malignant meningioma organoid models.

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Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions

Joao D. Pereira et al.

Summary: Researchers have successfully generated sensorimotor organoids derived from individuals with ALS, containing various cell types including skeletal muscle, sensory and motor neurons, astrocytes, microglia, and vasculature, forming neuromuscular junctions. These organoids demonstrate impairment at the NMJ level in ALS patients' iPSC lines and isogenic lines with familial ALS mutations, providing valuable insights into the pathophysiological mechanisms of ALS.

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Evolving Models and Tools for Microglial Studies in the Central Nervous System

Yang Zhang et al.

Summary: The key factors in the study of microglia are the choice of appropriate research models and associated tools, with mice being the most commonly used animal model. This review also summarizes the types of mouse and human-derived microglial research models, as well as recent developments in novel single-cell and in vivo imaging technologies.

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Developments in Biological Mechanisms and Treatments for Negative Symptoms and Cognitive Dysfunction of Schizophrenia

Qiongqiong Wu et al.

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Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Xianwei Chen et al.

Summary: This study established a human brain organoid-based sAD model using hiPSC-derived 3D brain organoids to mimic the serum exposure consequence of blood-brain barrier breakdown in AD patients. The model successfully recapitulated AD-like pathologies and could serve as a powerful platform for mechanistic study and therapeutic development in the future.

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DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome

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Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease

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Brain organoids get vascularized

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Genetically engineered cerebral organoids model brain tumor formation

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Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities

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Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients

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