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Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids.
Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type 1 male donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array (MEA) analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that increased SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in here identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing insights for optimizing treatment strategies.
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Personalized Human Astrocyte-Derived Region-Specific Forebrain Organoids Recapitulate Endogenous Pathological Features of Focal Cortical Dysplasia.
Focal cortical dysplasia (FCD) is a highly heterogeneous neurodevelopmental malformation, the underlying mechanisms of which remain largely elusive. In this study, personalized dorsal and ventral forebrain organoids (DFOs/VFOs) are generated derived from brain astrocytes of patients with FCD type II (FCD II). The pathological features of dysmorphic neurons, balloon cells, and astrogliosis are successfully replicated in patient-derived DFOs, but not in VFOs. It is noteworthy that cardiomyocyte-like cells correlated with dysmorphic neurons are generated through the high activation of BMP and WNT signaling in some of the FCD-organoids and patient cortical tissues. Moreover, functional assessments demonstrated the occurrence of epileptiform burst firing and propagative self-assembling neuronal hyperactivity in both FCD-DFOs and VFOs. Additionally, the heterotopic cardiomyocyte-organoids demonstrated the capacity for cardiomyocyte contraction and rhythmic firing. The presence of these cardiomyocytes contributes to the hyperactivity of neural networks in cardioids-DFOs assembly. In conclusion, the personalized region-specific forebrain organoids derived from FCD patient astrocytes effectively recapitulate heterogeneous pathological features, offering a valuable platform for the development of precise therapeutic strategies.
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Human heart organoids: current applications and future perspectives.
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Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms.
Esketamine, commonly used to treat treatment-resistant depression, has pharmacological mechanisms that remain incompletely understood. Brain organoids offer a human-relevant platform for investigating the cellular and molecular effects of drugs. In this study, we investigated the effects of esketamine on the electrophysiology and metabolism of brain organoids derived from iPSCs of healthy control subjects and depressed patients. Continuous monitoring revealed that esketamine treatment significantly decreased both the frequency and amplitude of action potentials, with the most pronounced reduction occurring within 4 h. High concentrations (1.5 mg/L) produced a stronger inhibitory effect, while organoids treated with a low concentration (0.25 mg/L) showed a recovery in action potential frequency after one week, although levels remained below pre-treatment values-a recovery not observed in the high-concentration group. Single-cell RNA sequencing demonstrated that esketamine modulated energy metabolism and induced metabolic reprogramming in a concentration- and time-dependent manner. Furthermore, by inhibiting oxidative phosphorylation and glycolysis separately and assessing cytosolic Ca2+ levels, we found that esketamine may regulate NMDAR activity and electrophysiology through energy metabolism pathways. These findings reveal a potential mechanism for esketamine's effects and offer new insights for clinical treatment strategies.
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A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders.
Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.
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[Effect of triftazin on the ultrastructure of neurons in the rat brain reticular formation].
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Cytochemical, stereological and radioautographic studies of rat raphe neurons.
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A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids.
Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our 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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Human 3D cellular model of hypoxic brain injury of prematurity.
Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.
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Generation of Human Ventral Midbrain Organoids Derived from Pluripotent Stem Cells.
Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is caused by the degeneration and loss of dopamine (DA) neurons in the ventral midbrain (VM). The focal and progressive degeneration of DA neurons in the VM makes PD a particularly attractive target for cell-based therapies. Human pluripotent stem cells (hPSCs) offer unprecedented opportunities to model the development and functional properties of human DA neurons in a dish. The use of human in vitro models based on hPSCs has empowered studies of VM development and provided access to neurons expressing a particular disease-specific phenotype. Currently, hPSC differentiation is most routinely carried out in monolayer cultures, which do not properly recapitulate cell-cell interactions and the structural complexity of the brain. Moreover, 2D cultures are challenging to maintain long term, as the cells tend to detach from the plate and lose their functional characteristics. This precludes the possibility of mimicking later phases of DA neurogenesis and recreating the complexity of functional neural circuitries. Here, we describe protocols showing how to maintain hPSCs in an undifferentiated state and how to then drive these hPSCs into 3D regionalized VM organoids. After long-term culture, these VM organoids exhibit mature and post-mitotic molecular features, including neuromelanin pigments similar to those released in primate VMs. We also report a protocol describing how to efficiently perform immunohistochemistry and how to detect neuromelanin-containing DA neurons in VM organoids. Together, these protocols provide a 3D in vitro platform that can be used to better understand the molecular mechanisms underlying DA neuron function and disease and may serve as a powerful tool for designing more targeted disease-modifying therapies. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Human pluripotent stem cell culture Basic Protocol 2: hPS cell differentiation for the generation of human ventral midbrain organoids Basic Protocol 3: Characterization of ventral midbrain organoids.