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Modeling Friedreich's ataxia with Bergmann glia-enriched human cerebellar organoids.
The human cerebellum is implicated in various neurological and psychiatric diseases, but its complex development and cellular diversity have posed challenges for in vitro modeling. Here, we report the generation of human induced pluripotent stem cell (iPSC)-derived cerebellar organoids (hCBOs) that are characterized by induction of rhombomere 1 (R1) cellular identity and followed by derivation of typical neuronal and glial cell types of the cerebellum. In contrast to forebrain organoids with multiple neural rosettes and inside-out neuronal migration, hCBOs develop a germinal zone on the outermost surface of the organoids with outside-in neuronal migration. These hCBOs produce various neuronal cell types resembling granule neurons, Purkinje cells, Golgi neurons, and deep cerebellar nuclei. By using a glial induction strategy, we generate Bergmann glial cells (BGCs) that serve as scaffolds for migratory granule cells and enhance electrophysiological activity of the hCBOs. Furthermore, by generating hCBOs from patients with Friedreich's ataxia (FRDA), we reveal disease-specific phenotypes that can be reversed by histone deacetylase (HDAC) inhibitors and gene editing by CRISPR-Cas9. Taken together, our advanced hCBO model provides new opportunities to investigate the mechanisms of cerebellar ontogenesis and utilize patient-derived iPSCs for translational research.
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Synapse formation and other ultrastructural features of postnatal development in the basilar pontine nuclei of the rat.
The postnatal development of the basilar pontine nuclei (BPN) was studied in the rat from birth through postnatal day 21. Although 3 maturational phases could be discerned within this time span, the events taking place within each phase overlap to some degree and the postnatal maturation of this region is best characterized as a continuum comprised of several simultaneously occurring processes. The early postnatal period (birth to postnatal day 5) is best described as a period of relative immaturity. Although generally similar to the adult BPN cytoarchitectonically, cell density in the early neonate is substantially higher than in the adult and this obscures to some degree the various subdivisions of the pontine gray. Neuronal somata are quite small in cross-sectional area relative to the adult and the neuropil is similarly immature and exhibits wide expanses of extracellular space and few synaptic boutons. These features are in marked contrast to the second developmental period which extends from postnatal days 6 through 13 and is characterized by an intense wave of synaptic proliferation. It is during this period that each of the various types of synaptic boutons that have been described in the adult make their appearance. Curiously, during this same time period, as well as in the early postnatal period, there also appears to be an ongoing process of spontaneous axon terminal elimination. The third developmental period begins on postnatal day 14 and extends through day 21 at which time the cytoarchitectonics, cytology and synaptic organization of the BPN are adult-like. During this period, no additional types of synaptic boutons appear, although the number of boutons continues to increase in a fairly uniform manner across all the various categories of synaptic boutons.
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Fine structure of growth cones in medullary raphe nuclei in the postnatal cat.
Morphological aspects of the dynamic processes of growth cone formation and synaptogenesis have been studied in neonatal kitten (2-17 days) medullary raphe nuclei. The formation and elaboration of dendritic growth cones and primary dendritic trunks is actively taking place on the medium size class neurons (stellates) of these nuclei. The dendritic growth cones are morphologically distinctive due to their population of large dense-core vesicles and postsynaptic position. Another growth cone morphology, interpreted as axonal, is also described. This growth cone is typically found in close association or synaptic contact with the dendritic growth cones and contains, in addition to synaptic vesicles, a dense-core vesicle population distinguishable from that of the dendritic growth cone by the presence of a variety of vesicles containing an eccentrically positioned dense particle. No evidence of axo-axonic or dendrodendritic synapses has been found. Synaptogenesis was found to be occurring on somas, dendrites and dendritic growth cones throughout the medullary raphe nuclei, though this phenomenon was more apparent in indistinctly localized subnuclear spaces termed synaptogenic zones. Within these zones large class neurons are found to have greater densities of both axodendritic and axosomatic synapses than medium and small class neurons respectively. Axodendritic synaptic densities on primary and secondary dendrites of large and medium class neurons are greater than their respective axosomatic synapse densities, which may suggest that the latter forms at a later period of development.
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Application of a high-density microelectrode array assay using a 3D human iPSC-derived brain microphysiological system model for in vitro neurotoxicity screening of environmental compounds.
Unraveling the associations between human exposure to environmental chemicals and potential neurotoxicity presents significant challenges. Evaluation of neurotoxicity potential using animal testing is resource-intensive (financial, labor, and animal use) and faces uncertainties regarding biological relevance to human health outcomes. Therefore, there is a need to develop efficient and human-relevant in vitro new approach methodologies (NAMs) to screen and evaluate chemicals for neurotoxicity potential. Recording of neural network activity using microelectrode array (MEA) technology has been identified as a reliable and reproducible method for evaluating neurotoxicity. Much of this research has been performed in 2D rodent-derived cell models. The 'BrainSpheres MEA assay' described in this study offers a promising functional human induced pluripotent stem cell (iPSC)-derived 3D brain model comprising neurons, astrocytes, and oligodendrocytes. We demonstrate consistent spontaneous neuronal firing and network bursting parameters from 7-week-old BrainSpheres using a high-density MEA technology. The performance of this model as a human-relevant NAM was evaluated by conducting a multi-concentration, 13 day exposure study with a set of ten chemicals. Neural activity metrics were assessed and compared to results from a 2D-MEA assay using rodent cells. Loperamide and domoic acid (two assay positive controls) demonstrated similar bioactivity profiles in the BrainSphere MEA assay to the 2D-MEA assay, while acetaminophen (assay negative control) was inactive in both assays. The 2D-MEA model demonstrated more potent bioactivity for 4/7 chemicals that were active in both assays. In the future, reducing replicate variability and testing a larger set of chemicals will likely improve the accuracy and reliability of the assay. These preliminary findings suggest that the BrainSphere assay could be used alongside the rat network formation assay (rNFA) as part of a tiered strategy, where hits in the rNFA are confirmed and further characterized in the BrainSphere model, helping move toward animal-free toxicological testing.
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Electronmicroscopic investigation of rat substantia nigra after chronic amphetamine treatment. I. Changes in the neurones.
The neurones in substantia nigra of albino rats were studied at ultrastructural level after chronic intraperitoneal administration of dl-amphetamine (5 mg/kg) for 90 days. Neurones with proliferated cytoplasmic organelles (granulated and smooth endoplasmic reticulum) were observed, as well as a tendency towards increase in the number of dense core vesicles. Very often it was possible to observe neurones with disorganization of the cytoplasmic organelles, with drastic decrease and disappearance of the dense core vesicles and simultaneous rise in the number and hypertrophy of the complex vesicles. Although less frequently, there also occur profiles with increased electron density and swelling of the astroglial growths in the adjacent neuropile.
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Structure-function correlation in mammalian neurosecretion.
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Pituitary organoids as models for congenital pituitary deficiencies.
Pituitary deficiencies, or hypopituitarisms, are defined as insufficient production of one or more adenohypophyseal hormones (growth hormone, TSH, ACTH, LH-FSH and prolactin). Congenital hypopituitarism, a rare disease with severely disabling consequences, often takes the form of isolated hormone deficiencies, such as isolated growth hormone deficiency (GHD) or isolated ACTH deficiency (ACTHD), or combined pituitary hormone deficiencies (CPHD), when several pituitary hormones are affected. They are mainly the result of genetic mutations, developmental malformations or the harmful action of environmental factors during foetal development. The last two decades have seen the emergence of new in vitro models called organoids, which make it possible to partially recreate the development of an organ using pluripotent cells. Using human embryonic stem cells (hESCs) or induced human embryonic stem cells (hiPSCs), it has been possible to recreate various stages of hypothalamic-pituitary development, a complex mechanism requiring interaction between two embryonic structures of different origins, right up to the production of functional pituitary endocrine cells. Coupled with techniques for reprogramming patients' somatic cells, these organoids have made it possible to understand the cellular and molecular mechanisms leading to the pathogenicity of a mutation in the OTX2 gene, identified as being responsible for CPHD. Using the CRISPR-CAS9 gene-editing technique, they have also demonstrated that the endocrine phenotype of patients suffering from DAVID syndrome is indeed linked to a mutation in the NFKB2 gene, thereby identifying this gene as a central element in pituitary development. Finally, the ability of these organoids to present a secretory response to hypothalamic stimulation and the possibility of modulating these signals by mimicking feedback from the target organs suggest that they could be used therapeutically.
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The fine structure of the choroid plexus in the musk rat.
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Stability of secretory granules containing growth hormone and prolactin from bovine anterior pituitary gland.
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Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models.
Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C experiments identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin three-dimensional (3D) interactions in SMS hiPSCs and 3D cortical organoids. Single-nucleus RNA sequencing of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell-cycle processes, and neuronal signaling. SMS cortical organoids displayed reduced growth, enlarged ventricles, impaired cell-cycle progression, and accelerated neuronal maturation. Through the use of a complementary hiPSC-derived 2D cortical neuronal model, we report that SMS cortical neurons exhibited accelerated dendritic growth, followed by neuronal hyperexcitability associated with reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell-cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.