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Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism.
This study investigated the impact of different bacterial populations on the biomolecular structures of cerebral organoids (COs) at various levels. COs were co-cultured with non-pathogenic (NM) and pathogenic (PM) bacterial populations. PM reduced the number of TUJ1+ neurons and disrupted the intact structure of COs. In addition, PM was found to induce changes in the transcript profile of COs, including a decrease in the activity of the glycolysis pathway and an increase in the pentose phosphate pathway, leading to deterioration in cellular energy metabolism, which is linked to neurodegenerative diseases. Proteomic analysis revealed a unique cluster of proteins in COs. PM exposure upregulated proteins related to neurological diseases, consistent with RNA-seq data. Communication between bacteria and neural cells was demonstrated using 18O-stable isotope labeling (SIL)-based metabolic flux analysis. COs showed higher 18O-enrichment of TCA cycle intermediates when co-cultured with NM and PM, indicating increased oxidative phosphorylation activity upon exposure to bacteria. This study provides a useful platform to monitor metabolic signals and communication between microbiotas and human brain cells. The findings suggest that pathogenic bacteria release metabolites that alter biomolecular structures in brain organoids, potentially contributing to neurodegenerative diseases.
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Engineering brain assembloids to interrogate human neural circuits.
The development of neural circuits involves wiring of neurons locally following their generation and migration, as well as establishing long-distance connections between brain regions. Studying these developmental processes in the human nervous system remains difficult because of limited access to tissue that can be maintained as functional over time in vitro. We have previously developed a method to convert human pluripotent stem cells into brain region-specific organoids that can be fused and integrated to form assembloids and study neuronal migration. In contrast to approaches that mix cell lineages in 2D cultures or engineer microchips, assembloids leverage self-organization to enable complex cell-cell interactions, circuit formation and maturation in long-term cultures. In this protocol, we describe approaches to model long-range neuronal connectivity in human brain assembloids. We present how to generate 3D spheroids resembling specific domains of the nervous system and then how to integrate them physically to allow axonal projections and synaptic assembly. In addition, we describe a series of assays including viral labeling and retrograde tracing, 3D live imaging of axon projection and optogenetics combined with calcium imaging and electrophysiological recordings to probe and manipulate the circuits in assembloids. The assays take 3-4 months to complete and require expertise in stem cell culture, imaging and electrophysiology. We anticipate that these approaches will be useful in deciphering human-specific aspects of neural circuit assembly and in modeling neurodevelopmental disorders with patient-derived cells.
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Exploring neuronal circuitry in neurodegenerative diseases: from traditional models to cutting-edge techniques.
Current treatments of neurodegenerative diseases primarily address symptoms rather than halting pathology progression. This gap is due to the lack of effective methods for monitoring neural circuitry and dynamics over time. In this context, the development of in vitro models that more accurately replicate the human brain microenvironment has become essential. Traditional two-dimensional (2D) cell cultures, while providing valuable insights, fail to capture the intricate complexity of the human brain. Recent advancements in neuroscience spotlight the emergence of more sophisticated three-dimensional (3D) models, which can more faithfully recapitulate the intricacies of the brain. This review discusses the evolution of in vitro brain models, emphasizing the transition from traditional 2D cultures to sophisticated 3D systems, including neurospheroids, brain organoids, assembloids and micro-tissue engineered neuronal networks (micro-TENNs). We further highlight the emergence of brain-on-chip platforms, combining microfluidics with cell culture technologies to create precisely controlled environments mimicking the physiological conditions of the human brain. Furthermore, we discuss the application of 3D bioprinting technology enabling the generation of neural constructs with precise control over cell placement. Lastly, we delve into the potential of integrating brain organoids with 3D bioprinting technology, aiming to recapitulate the true three-dimensional complexity of the brain, thereby improving the physiological accuracy of brain models for advancing our understanding of neurodegenerative diseases.
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Did lead poisoning help drive human evolution?
"Bold" hypothesis suggests tolerance for lead allowed Homo sapiens to outlive Neanderthals.
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Genetically Engineered Neoplastic Cerebral Organoids - A New Frontier in Preclinical Cancer Research.
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Electron microscope studies on the effect of 6-aminonicotinamide on mammalian embryos.
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Magnesium-calcium balances and steady states of biological systems.
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Revealing Tissue-Specific SARS-CoV-2 Infection and Host Responses using Human Stem Cell-Derived Lung and Cerebral Organoids.
COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.
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Choroid plexus organoids reveal mechanisms of Streptococcus suis translocation at the blood-cerebrospinal fluid barrier.
Streptococcus suis is a globally emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, S. suis must invade the central nervous system (CNS) by crossing the neurovascular unit, also known as the blood-brain barrier (BBB), or vascularized choroid plexus (ChP) epithelium known as the blood-cerebrospinal fluid barrier (BCSFB). Recently developed ChP organoids have been shown to accurately replicate the cytoarchitecture and physiological functions of the ChP epithelium in vivo. Here, we used human induced pluripotent stem cells (iPSC)-derived ChP organoids as an in vitro model to investigate S. suis interaction and infection at the BCSFB. Our study revealed that S. suis is capable of translocating across the epithelium of ChP organoids without causing significant cell death or compromising the barrier integrity. Plasminogen (Plg) binding to S. suis in the presence of tissue plasminogen activator (tPA), which converts immobilized Plg to plasmin (Pln), significantly increased the basolateral to apical translocation across ChP organoids into the CSF-like fluid in the lumen. S. suis was able to replicate at the same rate in CSF and laboratory S. suis culture medium but reached a lower final density. The analysis of transcriptomes in ChP organoids after S. suis infection indicated inflammatory responses, while the addition of Plg further suggested extracellular matrix (ECM) remodeling. To our knowledge, this is the first study using ChP organoids to investigate bacterial infection of the BCSFB. Our findings highlight the potential of ChP organoids as a valuable tool for studying the mechanisms of bacterial interaction and infection of the human ChP in vitro.
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Macro-bio-ethical Versus Micro-bio-ethical Issues Concerning Human Brain Organoids.