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Page 122 of 546-
Tanycytes: morphology and functions: a review.
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The liver as a potential gate to the brain for encephalitic viruses.
To model infection of viruses targeting the liver and the central nervous system, two-dimensional in vitro cultures rapidly show their limitations. Conversely, in vivo models do not easily allow the investigation of early events of the infection process. In between, ex vivo models, comprising mainly organoids and organotypic cultures, mimic or retain the cytoarchitecture of the organ while being relatively simple to handle and analyze. Here, we summarize the main features of brain and liver ex vivo models and pinpoint examples of their utilization for studying encephalitogenic and hepatotropic viruses. We highlight a gap of development and application of liver compared to ex vivo models in virology. Many hepatotropic viruses can also infect and/or have impacts on the central nervous system. In this sense, we sought to present these ex vivo models while providing a conceptual framework for the modeling of the hepatocerebral axis in the context of viral infections.
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Islet Amyloid Polypeptide Modelled to Simulate Diabetes Co-Oligomerized with β-Amyloid 1-42 Reproducing the Pathological Cascade of Alzheimer's Disease in Human Cerebral Organoids.
Previous animal models of sporadic Alzheimer's disease (sAD), based on the β-amyloid (Aβ) cascade hypothesis and induced by Aβ1-42 oligomers (AβO), only recapitulated early AD pathological features. sAD cerebral organoids (COs) model employed Aβ coculture approach and found no typical features of AD pathology. Type 2 diabetes (T2DM) is one of the most important modifiable AD risk factors, so we hypothesize that T2DM could substantially exacerbate Aβ neurotoxicity and reproduce typical AD pathology. Human islet amyloid polypeptide (hIAPP) was used to mimic T2DM and was co-oligomerized with Aβ1-42 peptide, and delivered to the central of human iPSC-derived mature COs through intermittently repeated microinjections, so as to simulate the chronic exposure to Aβ within the brain. The Aβ42-hIAPP co-oligomers induced a pathological phenotype more closely resembling the pathological features of advanced AD, notably, neuronal density showed significant reduction, with 3.2 times more neuronal death. Dynamic metabolomic analysis revealed the metabolic pathways and differential metabolites that may be correlated to the primary mechanism underlying the enhanced neurotoxic effects and accelerated AD pathology. Furthermore, this study developed a sAD CO model more resembling the pathological features of advanced AD, which potentially provides a valuable platform for AD pathogenesis research and novel drug screening.
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Astrocyte-secreted cues promote neural maturation and augment activity in human forebrain organoids.
Brain organoids have been proposed as suitable human brain model candidates for a variety of applications. However, the lack of appropriate maturation limits the transferability of such functional tools. Here, we present a method to facilitate neuronal maturation by integrating astrocyte-secreted factors into hPSC-derived 2D and 3D neural culture systems. We demonstrate that protein- and nutrient-enriched astrocyte-conditioned medium (ACM) accelerates neuronal differentiation with enlarged neuronal layer and the overproduction of deep-layer cortical neurons. We captured the elevated changes in the functional activity of neuronal networks within ACM-treated organoids using comprehensive electrophysiological recordings. Furthermore, astrocyte-secreted cues can induce lipid droplet accumulation in neural cultures, offering protective effects in neural differentiation to withstand cellular stress. Together, these data indicate the potential of astrocyte secretions to promote neural maturation.
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Structural aspects of brain barriers, with special reference to the permeability of the cerebral endothelium and choroidal epithelium.
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Modeling Traumatic Brain Injury in Human Cerebral Organoids.
Traumatic brain injury (TBI) is a head injury that disrupts the normal brain structure and function. TBI has been extensively studied using various in vitro and in vivo models. Most of the studies have been done with rodent models, which may respond differently to TBI than human nerve cells. Taking advantage of the recent development of cerebral organoids (COs) derived from human induced pluripotent stem cells (iPSCs), which resemble the architecture of specific human brain regions, here, we adapted the controlled cortical impact (CCI) model to induce TBI in human COs as a novel in vitro platform. To adapt the CCI procedure into COs, we have developed a phantom brain matrix, matching the mechanical characteristics of the brain, altogether with an empty mouse skull as a platform to allow the use of the stereotactic CCI equipment on COs. After the CCI procedure, COs were histologically prepared to evaluate neurons and astrocyte populations using the microtubule-associated protein 2 (MAP2) and the glial fibrillary acidic protein (GFAP). Moreover, a marker of metabolic response, the neuron-specific enolase (NSE), and cellular death using cleaved caspase 3 were also analyzed. Our results show that human COs recapitulate the primary pathological changes of TBI, including metabolic alterations related to neuronal damage, neuronal loss, and astrogliosis. This novel approach using human COs to model TBI in vitro holds great potential and opens new alternatives for understanding brain abnormalities produced by TBI, and for the development and testing of new therapeutic approaches.
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Which organelles are necessary for fast neuronal transport?
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APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.
Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, APOE4 causes persistent changes in brain structure as early as infancy and is associated with altered functional connectivity that extends beyond adolescence. Here, we used human induced pluripotent stem cell-derived cortical and ganglionic eminence organoids (COs and GEOs) to examine APOE4's influence during the development of cortical excitatory and inhibitory neurons. We show that APOE4 reduces cortical neurons and increases glia by promoting gliogenic transcriptional programs. In contrast, APOE4 increases proliferation and differentiation of GABAergic progenitors resulting in early and persistent increases in GABAergic neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupts neural network function resulting in heightened excitability and synchronicity. Together, our data provide new insights on how APOE4 influences cortical neurodevelopmental processes and the establishment of functional networks.
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The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.
Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.
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High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.