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Context matters: hPSC-derived microglia thrive in a humanized brain environment in vivo.
It remains challenging to create a physiologically relevant human-brain-like environment that would support maturation of human pluripotent stem cell (hPSC)-derived microglia (hMGs). Schafer et al.1 (Cell, 2023) now develop an in vivo neuroimmune organoid model with mature homeostatic hMGs for the study of brain development and disease.
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3D human brain cell models: New frontiers in disease understanding and drug discovery for neurodegenerative diseases.
Neurodegenerative disorders have an enormous impact on society and healthcare budgets. There has been a high degree of failure in many recent clinical trials for disease-modifying therapeutics. A major factor in this failure is the difficulty of translating findings from animal-based cell models to human patients. The majority of non-animal neurodegenerative disease research has been conducted in 2 dimensional models of rodent neonatal neurons and glia. While these systems have provided valuable insights into neural cell function and dysfunction, they have largely reached the end of their useful life, as human stem cell technologies combined with major advances in microfluidic technologies have opened the door to development of patient-derived 3D brain cell models. These have major advantages in providing a micro-physiological system more closely reflecting the in vivo brain environment, and promote the interaction between different patient-derived brain cell-types. However, major challenges remain before these model systems will replace the 2D rodent models as the workhorse for neurodegenerative disease studies. Despite these challenges, we are likely to experience a rapid transition of research from old models to new patient derived 3D brain cell systems, which will likely improve translational outcomes for disease therapeutics.
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Single-Cell Transcriptomics Supports a Role of CHD8 in Autism.
Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of "when, why and how cells deviate from their normal trajectories". High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell's biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of Chd8/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.
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The End of Personification: The Mereological Fallacy in Science Communication on Brain Organoids.
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Glioblastoma preclinical models: Strengths and weaknesses.
Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.
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Applications of Induced Pluripotent Stem Cell-Derived Glia in Brain Disease Research and Treatment.
Glia are integral components of neural networks and are crucial in both physiological functions and pathological processes of the brain. Many brain diseases involve glial abnormalities, including inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. Induced pluripotent stem cell (iPSC)-derived glia provide opportunities to study the contributions of glia in human brain diseases. These cells have been used for human disease modeling as well as generating new therapies. This chapter introduces glial involvement in brain diseases, then summarizes different methods of generating iPSC-derived glia disease models of these cells. Finally, strategies for treating disease using iPSC-derived glia are discussed. The goal of this chapter is to provide an overview and shed light on the applications of iPSC-derived glia in brain disease research and treatment.
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Modular tissue-in-a-CUBE platform to model blood-brain barrier (BBB) and brain interaction.
With the advent of increasingly sophisticated organoids, there is growing demand for technology to replicate the interactions between multiple tissues or organs. This is challenging to achieve, however, due to the varying culture conditions of the different cell types that make up each tissue. Current methods often require complicated microfluidic setups, but fragile tissue samples tend not to fare well with rough handling. Furthermore, the more complicated the human system to be replicated, the more difficult the model becomes to operate. Here, we present the development of a multi-tissue chip platform that takes advantage of the modularity and convenient handling ability of a CUBE device. We first developed a blood-brain barrier-in-a-CUBE by layering astrocytes, pericytes, and brain microvascular endothelial cells in the CUBE, and confirmed the expression and function of important tight junction and transporter proteins in the blood-brain barrier model. Then, we demonstrated the application of integrating Tissue-in-a-CUBE with a chip in simulating the in vitro testing of the permeability of a drug through the blood-brain barrier to the brain and its effect on treating the glioblastoma brain cancer model. We anticipate that this platform can be adapted for use with organoids to build complex human systems in vitro by the combination of multiple simple CUBE units.
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Nuclear proteome reveals microtubule-associated protein regulating fate and disease.
Cellular differentiation and morphogenesis require the coordination between cytoskeletal remodeling and transcriptional programs, raising the question of how cytoskeletal information is conveyed to the nucleus. Here, we profile the nuclear and cytosolic proteome of human and murine neural stem cells (NSCs) and uncover abundant cytoskeletal proteins in the nucleus, including the microtubule-associated protein 1B (MAP1B), implicated in disease. We find that MAP1B shuttles to the nucleus where it interacts with the BRG1-containing chromatin remodeling complex. MAP1B's nuclear enrichment promotes NSC fate, as opposed to its cytosolic function promoting neuronal differentiation. In vivo, increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of patients with MAP1B mutations. Mutant human brain organoids show aberrant MAP1B nuclear enrichment, enhanced BRG1 chromatin binding, and neuronal ectopia formation. Our study uncovers a nuclear pool of cytoskeleton-associated proteins, revealing their role in fate regulation during brain development and reshaping our understanding of neurodevelopmental disease etiology.
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DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development.
DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segregation in favor of alternative pathways that depend on TOPBP1 and CIP2A, but how these pathways function is still poorly defined. Here, we describe the identification of DDIAS as a mitosis-specific DNA damage response protein. We establish DDIAS as a phosphorylation-dependent component and effector of the TOPBP1-CIP2A complex, and we demonstrate that DDIAS protects single-stranded DNA from aberrant nucleolytic processing to safeguard chromosome integrity during mitosis, particularly in BRCA1-/BRCA2-deficient cells. We also identify biallelic inactivating mutations in DDIAS in patients with a severe neurodevelopmental disorder and, using human cerebral organoids and zebrafish, we show that DDIAS plays a critical and evolutionarily conserved role in limiting DNA damage specifically in neural progenitor cells. These findings demonstrate a physiological role for the DNA damage response in mitosis during vertebrate neurodevelopment.
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Cerebral malaria - modelling interactions at the blood-brain barrier in vitro.
The blood-brain barrier (BBB) is a continuous endothelial barrier that is supported by pericytes and astrocytes and regulates the passage of solutes between the bloodstream and the brain. This structure is called the neurovascular unit and serves to protect the brain from blood-borne disease-causing agents and other risk factors. In the past decade, great strides have been made to investigate the neurovascular unit for delivery of chemotherapeutics and for understanding how pathogens can circumvent the barrier, leading to severe and, at times, fatal complications. One such complication is cerebral malaria, in which Plasmodium falciparum-infected red blood cells disrupt the barrier function of the BBB, causing severe brain swelling. Multiple in vitro models of the BBB are available to investigate the mechanisms underlying the pathogenesis of cerebral malaria and other diseases. These range from single-cell monolayer cultures to multicellular BBB organoids and highly complex cerebral organoids. Here, we review the technologies available in malaria research to investigate the interaction between P. falciparum-infected red blood cells and the BBB, and discuss the advantages and disadvantages of each model.