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Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.
Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.
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Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum.
Brain neurons arise from relatively few progenitors generating an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis is thought to be that excitatory and inhibitory neurons derive from separate, spatially segregated progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both lineages exist and how such a fate decision may be regulated are unknown. Using cerebellar development as a model, we discover that individual progenitors can give rise to both inhibitory and excitatory lineages. Gradations of Notch activity determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate, while intermediate levels of Notch activity generate inhibitory neurons, and daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors.
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iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.
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The rise of three-dimensional human brain cultures.
Pluripotent stem cells show a remarkable ability to self-organize and differentiate in vitro in three-dimensional aggregates, known as organoids or organ spheroids, and to recapitulate aspects of human brain development and function. Region-specific 3D brain cultures can be derived from any individual and assembled to model complex cell-cell interactions and to generate circuits in human brain assembloids. Here I discuss how this approach can be used to understand unique features of the human brain and to gain insights into neuropsychiatric disorders. In addition, I consider the challenges faced by researchers in further improving and developing methods to probe and manipulate patient-derived 3D brain cultures.
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Neurorestorative Approaches for Ischemic StrokeChallenges, Opportunities, and Recent Advances.
Despite recent advances in acute stroke management, most patients experiencing a stroke will suffer from residual brain damage and functional impairment. Addressing those residual deficits would require neurorestoration, i.e., rebuilding brain tissue to repair the structural brain damage caused by stroke. However, there are major pathobiological, anatomical and technological hurdles making neurorestorative approaches remarkably challenging, and true neurorestoration after larger ischemic lesions could not yet be achieved. On the other hand, there has been steady advancement in our understanding of the limits of tissue regeneration in the adult mammalian brain as well as of the fundamental organization of brain tissue growth during embryo- and ontogenesis. This has been paralleled by the development of novel animal models to study stroke, advancement of biomaterials that can be used to support neurorestoration, and in stem cell technologies. This review gives a detailed explanation of the major hurdles so far preventing the achievement of neurorestoration after stroke. It will also describe novel concepts and advancements in biomaterial science, brain organoid culturing, and animal modeling that may enable the investigation of post-stroke neurorestorative approaches in translationally relevant setups. Finally, there will be a review of recent achievements in experimental studies that have the potential to be the starting point of research and development activities that may eventually bring post-stroke neurorestoration within reach.
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Modeling brain and neural crest neoplasms with human pluripotent stem cells.
Pluripotent stem cells offer unique avenues to study human-specific aspects of disease and are a highly versatile tool in cancer research. Oncogenic processes and developmental programs often share overlapping transcriptomic and epigenetic signatures, which can be reactivated in induced pluripotent stem cells. With the emergence of brain organoids, the ability to recapitulate brain development and structure has vastly improved, making in vitro models more realistic and hence more suitable for biomedical modeling. This review highlights recent research and current challenges in human pluripotent stem cell modeling of brain and neural crest neoplasms, and concludes with a call for more rigorous quality control and for the development of models for rare tumor subtypes.
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Modeling human neurodevelopmental diseases with brain organoids.
Studying the etiology of human neurodevelopmental diseases has long been a challenging task due to the brain's complexity and its limited accessibility. Human pluripotent stem cells (hPSCs)-derived brain organoids are capable of recapitulating various features and functionalities of the human brain, allowing the investigation of intricate pathogenesis of developmental abnormalities. Over the past years, brain organoids have facilitated identifying disease-associated phenotypes and underlying mechanisms for human neurodevelopmental diseases. Integrating with more cutting-edge technologies, particularly gene editing, brain organoids further empower human disease modeling. Here, we review the latest progress in modeling human neurodevelopmental disorders with brain organoids.
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Human In Vitro Models of Neuroenergetics and Neurometabolic Disturbances: Current Advances and Clinical Perspectives.
Neurological conditions conquer the world; they are the leading cause of disability and the second leading cause of death worldwide, and they appear all around the world in every age group, gender, nationality, and socioeconomic class. Despite the growing evidence of an immense impact of perturbations in neuroenergetics on overall brain function, only little is known about the underlying mechanisms. Especially human insights are sparse, owing to a shortage of physiologically relevant model systems. With this perspective, we aim to explore the key steps and considerations involved in developing an advanced human in vitro model for studying neuroenergetics. We discuss biological and technological strategies to meet the requirements of a predictive model, aiming at providing a guide and inspiration for future in vitro models of neuroenergetics.
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TMEM161B modulates radial glial scaffolding in neocortical development.
TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.
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The TREX1 Dinosaur Bites the Brain through the LINE.
In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi-Goutières syndrome in the neural system.