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Neuron-Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures.
Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation/inhibition balance (E/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.
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Cortical Organoids to Model Microcephaly.
How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man's place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.
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Reaching into the toolbox: Stem cell models to study neuropsychiatric disorders.
Recent advances in genetics, molecular biology, and stem cell biology have accelerated our understanding of neuropsychiatric disorders, like autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). This progress highlights the incredible complexity of both the human brain and mental illnesses from the biochemical to the cellular level. Contributing to the complexity of neuropsychiatric disorders are their polygenic nature, cellular and brain region interconnectivity, and dysregulation of human-specific neurodevelopmental processes. Here, we discuss available tools, including CRISPR-Cas9, and the applications of these tools to develop cell-based two-dimensional (2D) models and 3D brain organoid models that better represent and unravel the intricacies of neuropsychiatric disorder pathophysiology.
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The Imperative for Innovative Enteric Nervous System-Intestinal Organoid Co-Culture Models: Transforming GI Disease Modeling and Treatment.
This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves as an introduction to the companion protocol paper featured in this journal. The protocol outlines the isolation and co-culture of myenteric and submucosal neurons with small intestinal organoids. This review provides an overview of the intestinal organoid culture field to establish a solid foundation for effective protocol application. Remarkably, the ENS surpasses the number of neurons in the spinal cord. Referred to as the "second brain", the ENS orchestrates pivotal roles in GI functions, including motility, blood flow, and secretion. The ENS is organized into myenteric and submucosal plexuses. These plexuses house diverse subtypes of neurons. Due to its proximity to the gut musculature and its cell type complexity, there are methodological intricacies in studying the ENS. Diverse approaches such as primary cell cultures, three-dimensional (3D) neurospheres, and induced ENS cells offer diverse insights into the multifaceted functionality of the ENS. The ENS exhibits dynamic interactions with the intestinal epithelium, the muscle layer, and the immune system, influencing epithelial physiology, motility, immune responses, and the microbiome. Neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), and vasoactive intestinal peptide (VIP), play pivotal roles in these intricate interactions. Understanding these dynamics is imperative, as the ENS is implicated in various diseases, ranging from neuropathies to GI disorders and neurodegenerative diseases. The emergence of organoid technology presents an unprecedented opportunity to study ENS interactions within the complex milieu of the small and large intestines. This manuscript underscores the urgent need for standardized protocols and advanced techniques to unravel the complexities of the ENS and its dynamic relationship with the gut ecosystem. The insights gleaned from such endeavors hold the potential to revolutionize GI disease modeling and treatment paradigms.
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Dosage Counts: Correcting Trisomy-21-Related Phenotypes in Human Organoids and Xenografts.
Studies in mice suggest that Olig2 gene dosage alters cerebral cortical interneuron development and contributes to trisomy-21/Down-syndrome-related intellectual disability. Xu et al. (2019) extend these studies through the remarkable use of cerebral organoid and human iPSC/mouse brain chimera experimental systems that provide an opportunity for the development of novel therapeutics.
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Research progress of lung organoids in infectious respiratory diseases.
Infectious respiratory diseases are common epidemics that often exhibit phased outbreaks, increasing the healthcare burden. Past research models for these diseases were relatively simplistic, but the emergence of organoids has transformed this landscape. Organoids, three-dimensional in vitro tissue analogs that recapitulate specific spatial organ structures derived from stem cell culture, have advanced significantly over the decade since their inception. Compared to conventional animal models, organoids circumvent interspecies variations, enabling a more precise representation of human physiological and pathological traits. Relative to two-dimensional cell cultures, organoids exhibit enhanced complexity, incorporating diverse cell types and maintaining stable genomes, which facilitates a more faithful simulation of cellular interactions within the extracellular microenvironment. Consequently, as a three-dimensional in vitro model, lung organoids are pivotal for investigating lung organ development, infectious disease pathogenesis, and drug screening. Although SARS-CoV-2 is receding from the spotlight, advancing lung organoid development for addressing infectious respiratory diseases like influenza remains a priority. This review demonstrated the differentiation culture process of lung organoids and outlined advancements in utilizing organoids to elucidate pathogenic infection mechanisms, reveal virus-host interactions and screen therapeutic drugs over the past seven years. Additionally, we have summarized the advances in lung organoid model technologies and outlined their developmental directions.
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Neuromuscular Organoids to Study Spinal Cord Development and Disease.
Many aspects of neurodegenerative disease pathology remain unresolved. Why do certain neuronal subpopulations acquire vulnerability to stress or mutations in ubiquitously expressed genes, while others remain resilient? Do these neurons harbor intrinsic marks that make them prone to degeneration? Do these diseases have a neurodevelopmental component? Lacking this fundamental knowledge hampers the discovery of efficacious treatments. While it is well established that human organoids enable the modeling of brain-related diseases, we still lack an organoid model that recapitulates the regionalization complexity and physiology of the spinal cord. Here, we describe an advanced experimental protocol to generate neuromuscular organoids composed of a wide rostro-caudal (RC) diversity of spinal motor neurons (spMNs) and mesodermal progenitor-derived muscle cells. This model therefore allows for the robust and reproducible study of neuromuscular unit development and disease.
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Biofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids.
Human neural organoid models have become an important tool for studying neurobiology. However, improving the representativeness of neural cell populations in such organoids remains a major effort. In this work, we compared Matrigel, a commercially available matrix, to a neural cadherin (N-cadherin) peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. We determined that peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad hydrogels mapped more closely to human fetal populations and produced neurons with more spontaneous excitatory postsynaptic currents relative to Matrigel. These results provide compelling evidence that matrix-tethered signaling peptides can influence neural organoid differentiation, opening an avenue to control stem cell fate. Moreover, outcomes from this work showcase the technical utility of GelMA-Cad as a simple and defined hydrogel alternative to Matrigel for neural organoid culture.
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Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells.
Inner ear sensory epithelia contain mechanosensitive hair cells that transmit information to the brain through innervation with bipolar neurons. Mammalian hair cells do not regenerate and are limited in number. Here we investigate the potential to generate mechanosensitive hair cells from mouse embryonic stem cells in a three-dimensional (3D) culture system. The system faithfully recapitulates mouse inner ear induction followed by self-guided development into organoids that morphologically resemble inner ear vestibular organs. We find that organoid hair cells acquire mechanosensitivity equivalent to functionally mature hair cells in postnatal mice. The organoid hair cells also progress through a similar dynamic developmental pattern of ion channel expression, reminiscent of two subtypes of native vestibular hair cells. We conclude that our 3D culture system can generate large numbers of fully functional sensory cells which could be used to investigate mechanisms of inner ear development and disease as well as regenerative mechanisms for inner ear repair.
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Harnessing Decellularized Extracellular Matrix for Enhanced Fidelity in Colorectal Cancer Organoid and Cell-Derived Xenograft Models.
This study evaluates the efficacy of a decellularized intestine tissue-derived extracellular matrix (Intestine ECM) as a scaffold for culturing colorectal cancer (CRC) organoids and establishing cell-derived xenograft (CDX) models, comparing its performance to traditional Matrigel. Intestine ECM demonstrates comparable support for organoid formation and cellular function, highlighting its potential as a more physiologically relevant and reproducible platform. Our findings suggest that Intestine ECM enhances the mimetic environment for colon epithelium, supporting comparable growth and improved differentiation compared to Matrigel. Moreover, when used as a delivery carrier, Intestine ECM significantly increases the growth rate of CDX models using patient-derived primary colorectal cancer cells. This enhancement demonstrates Intestine ECM's role not only as a scaffold but also as a vital component of the tumor microenvironment, facilitating more robust tumorigenesis. These findings advocate for the broader application of Intestine ECM in cancer model systems, potentially leading to more accurate preclinical evaluations and the development of targeted cancer therapies.