Organoid
organoid
A human stem cell-derived organoid model of the trigeminal ganglion
PD Dr. Zohreh Hosseinzadeh
PhD position in retina research for ERC grant project Join a 3-year PhD program in retinal development and immerse yourself in cutting-edge research to unlock the secrets of the human retina organoids from stem cells. With state-of-the-art techniques, you'll have the opportunity to make a real impact by developing innovative solutions for ocular diseases. Advance your career and change the future of eye care: This program offers you a unique opportunity to be at the forefront of scientific discovery. Apply now and take your passion and creativity to the next level! What we are looking for a PhD candidate for the position: • An excellent academic record • Experimental knowledge in electrophysiology (patch clamp, multi-electrode array) , ideally in functional imaging, cell/tissue culture or molecular biology is an advantage • A solid background in biology, ideally in neuroscience • Background in statistics and data analysis • Programming experience in Python, Matlab, R or similar is ideal • Personal skills: The applicant must have a good organizational skills, and the ability to work autonomously, but willing to perform and interact efficiently within a multidisciplinary team. What we offer: A friendly, stimulating, international and multidisciplinary environment. Leipzig has beautiful nature, perfect for hiking, biking, and swimming. The successful candidate will be enrolled in the Graduate School for Brain Dynamics of the Leipzig University. The application package is expected to contain: • A CV • The motivation for applying to this position • Two reference letters • master certificate Please send the documents to Zohreh.Hosseinzadeh@medizin.uni-leipzig.de (PD Dr. Zohreh Hosseinzadeh); Focke.Ziemssen@medizin.uni-leipzig.de (Prof. Focke Ziemssen)
Modeling human brain development and disease: the role of primary cilia
Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.
Cellular crosstalk in Neurodevelopmental Disorders
Cellular crosstalk is an essential process during brain development and it is influenced by numerous factors, including the morphology of the cells, their adhesion molecules, the local extracellular matrix and the secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the correct development of the human brain. Hence, we combine the in vivo mouse model and the in vitro human-derived neurons, cerebral organoids, and dorso-ventral assembloids in order to better comprehend the molecular and cellular mechanisms involved in ventral progenitors’ proliferation and fate as well as migration and maturation of inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders. We particularly focus on mutations in genes influencing cell-cell contacts, extracellular matrix, and secretion of vesicles and therefore study intrinsic and extrinsic mechanisms contributing to the formation of the brain. Our data reveal an important contribution of cell non-autonomous mechanisms in the development of neurodevelopmental disorders.
Organoid-based single-cell spatiotemporal gene expression landscape of human embryonic development and hematopoiesis
Integration of 3D human stem cell models derived from post-mortem tissue and statistical genomics to guide schizophrenia therapeutic development
Schizophrenia is a neuropsychiatric disorder characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as avolition and withdrawal) and cognitive dysfunction1. Schizophrenia is highly heritable, and genetic studies are playing a pivotal role in identifying potential biomarkers and causal disease mechanisms with the hope of informing new treatments. Genome-wide association studies (GWAS) identified nearly 270 loci with a high statistical association with schizophrenia risk; however each locus confers only a small increase in risk therefore it is difficult to translate these findings into understanding disease biology that can lead to treatments. Induced pluripotent stem cell (iPSC) models are a tractable system to translate genetic findings and interrogate mechanisms of pathogenesis. Mounting research with patient-derived iPSCs has proposed several neurodevelopmental pathways altered in SCZ, such as neural progenitor cell (NPC) proliferation, imbalanced differentiation of excitatory and inhibitory cortical neurons. However, it is unclear what exactly these iPS models recapitulate, how potential perturbations of early brain development translates into illness in adults and how iPS models that represent fetal stages can be utilized to further drug development efforts to treat adult illness. I will present the largest transcriptome analysis of post-mortem caudate nucleus in schizophrenia where we discovered that decreased presynaptic DRD2 autoregulation is the causal dopamine risk factor for schizophrenia (Benjamin et al, Nature Neuroscience 2022 https://doi.org/10.1038/s41593-022-01182-7). We developed stem cell models from a subset of the postmortem cohort to better understand the molecular underpinnings of human psychiatric disorders (Sawada et al, Stem Cell Research 2020). We established a method for the differentiation of iPS cells into ventral forebrain organoids and performed single cell RNAseq and cellular phenotyping. To our knowledge, this is the first study to evaluate iPSC models of SZ from the same individuals with postmortem tissue. Our study establishes that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development. Differentiation of inhibitory neurons is accelerated whereas excitatory neuronal development is delayed, implicating an excitation and inhibition (E-I) imbalance during early brain development in SCZ. We found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Altogether, we demonstrate that ventral forebrain organoids derived from postmortem tissue of individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donors’ brains (Sawada et al, biorxiv 2022 https://doi.org/10.1101/2022.05.26.493589).
Untitled Seminar
Heiko Luhmann (Germany) – How neuronal activity builds the cerebral cortex; Mary Tolcos (Australia) – Cortical development and fetal brain injury; Silvia Velasco (Australia) – Human brain organoids to study neurodevelopment and disease
Investigating activity-dependent processes in cerebral cortex development and disease
The cerebral cortex contains an extraordinary diversity of excitatory projection neuron (PN) and inhibitory interneurons (IN), wired together to form complex circuits. Spatiotemporally coordinated execution of intrinsic molecular programs by PNs and INs and activity-dependent processes, contribute to cortical development and cortical microcircuits formation. Alterations of these delicate processes have often been associated to neurological/neurodevelopmental disorders. However, despite the groundbreaking discovery that spontaneous activity in the embryonic brain can shape regional identities of distinct cortical territories, it is still unclear whether this early activity contributes to define subtype-specific neuronal fate as well as circuit assembly. In this study, we combined in utero genetic perturbations via CRISPR/Cas9 system and pharmacological inhibition of selected ion channels with RNA-sequencing and live imaging technologies to identify the activity-regulated processes controlling the development of different cortical PN classes, their wiring and the acquisition of subtype specific features. Moreover, we generated human induced pluripotent stem cells (iPSCs) form patients affected by a severe, rare and untreatable form of developmental epileptic encephalopathy. By differentiating cortical organoids form patient-derived iPSCs we create human models of early electrical alterations for studying molecular, structural and functional consequences of the genetic mutations during cortical development. Our ultimate goal is to define the activity-conditioned processes that physiologically occur during the development of cortical circuits, to identify novel therapeutical paths to address the pathological consequences of neonatal epilepsies.
Exploring mechanisms of human brain expansion in cerebral organoids
The human brain sets us apart as a species, with its size being one of its most striking features. Brain size is largely determined during development as vast numbers of neurons and supportive glia are generated. In an effort to better understand the events that determine the human brain’s cellular makeup, and its size, we use a human model system in a dish, called cerebral organoids. These 3D tissues are generated from pluripotent stem cells through neural differentiation and a supportive 3D microenvironment to generate organoids with the same tissue architecture as the early human fetal brain. Such organoids are allowing us to tackle questions previously impossible with more traditional approaches. Indeed, our recent findings provide insight into regulation of brain size and neuron number across ape species, identifying key stages of early neural stem cell expansion that set up a larger starting cell number to enable the production of increased numbers of neurons. We are also investigating the role of extrinsic regulators in determining numbers and types of neurons produced in the human cerebral cortex. Overall, our findings are pointing to key, human-specific aspects of brain development and function, that have important implications for neurological disease.
Reversing autism-related phenotypes in human brain organoids
2nd In-Vitro 2D & 3D Neuronal Networks Summit
The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.
2nd In-Vitro 2D & 3D Neuronal Networks Summit
The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.
Retinal neurogenesis and lamination: What to become, where to become it and how to move from there!
The vertebrate retina is an important outpost of the central nervous system, responsible for the perception and transmission of visual information. It consists of five different types of neurons that reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Unsurprisingly, impaired fate decisions as well as impaired neuronal migrations and lamination lead to impaired retinal function. However, how processes are coordinated at the cellular and tissue level and how variable or robust retinal formation is, is currently still underexplored. In my lab, we aim to shed light on these questions from different angles, studying on the one hand differentiation phenomena and their variability and on the other hand the downstream migration and lamination phenomena. We use zebrafish as our main model system due to its excellent possibilities for live imaging and quantitative developmental biology. More recently we also started to use human retinal organoids as a comparative system. We further employ cross disciplinary approaches to address these issues combining work of cell and developmental biology, biomechanics, theory and computer science. Together, this allows us to integrate cell with tissue-wide phenomena and generate an appreciation of the reproducibility and variability of events.
One by one: brain organoid modelling of neurodevelopmental disorders at single cell resolution
Epigenetic regulation of human brain organoid development in single cells
Synaptic alterations in the striatum drive ASD-related behaviors in mice
Stem cell approaches to understand acquired and genetic epilepsies
The Hsieh lab focuses on the mechanisms that promote neural stem cell self-renewal and differentiation in embryonic and adult brain. Using mouse models, video-EEG monitoring, viral techniques, and imaging/electrophysiological approaches, we elucidated many of the key transcriptional/epigenetic regulators of adult neurogenesis and showed aberrant new neuron integration in adult rodent hippocampus contribute to circuit disruption and seizure development. Building on this work, I will present our recent studies describing how GABA-mediated Ca2+ activity regulates the production of aberrant adult-born granule cells. In a new direction of my laboratory, we are using human induced pluripotent stem cells and brain organoid models as approaches to understand brain development and disease. Mutations in one gene, Aristaless-related homeobox (ARX), are of considerable interest since they are known to cause a common spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual disability. We have generated cortical and subpallial organoids from patients with poly-alanine expansion mutations in ARX. To understand the nature of ARX mutations in the organoid system, we are currently performing cellular, molecular, and physiological analyses. I will present these data to gain a comprehensive picture of the effect of ARX mutations in brain development. Since we do not understand how human brain development is affected by ARX mutations that contribute to epilepsy, we believe these studies will allow us to understand the mechanism of pathogenesis of ARX mutations, which has the potential to impact the diagnosis and care of patients.
Modeling human neurodevelopment and evolution using brain organoids
Using Human Stem Cells to Uncover Genetic Epilepsy Mechanisms
Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an increasingly utilized approach for neurological disease modeling with patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. Although most studies to date involve 2-D cultures of patient-derived neurons, brain organoids are increasingly being employed to explore genetic DEE mechanisms. We are applying this approach to understand PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome, Rett Syndrome (in collaboration with Ben Novitch at UCLA) and Protocadherin-19 Clustering Epilepsy (PCE). I will describe our findings of robust structural phenotypes in PMSE and PCE patient-derived brain organoid models, as well as functional abnormalities identified in fusion organoid models of Rett syndrome. In addition to showing epilepsy-relevant phenotypes, both 2D and brain organoid cultures offer platforms to identify novel therapies. We will also discuss challenges and recent advances in the brain organoid field, including a new single rosette brain organoid model that we have developed. The field is advancing rapidly and our findings suggest that brain organoid approaches offers great promise for modeling genetic neurodevelopmental epilepsies and identifying precision therapies.
Reproducible research using stem cell derived neurons and organoids
Reconstructing human brain organoid development with single-cell analyses
Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids
The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points.
Synthetic Developmental Biology - Cross-species comparison and manipulation of organoids
Retinal organoids from pluripotent stem cells: from development to disease
Modeling human development and disease in cerebral organoids
Brain Organoids and Next-Generation Assembloid Models to Study Human Development and Disease
Rethinking neuroconstructivism through brain organoids at single cell resolution
Multiplexing and Demultiplexing with cerebral organoids for neurological diseases
Intrinsic and extrinsic regulators of human brain size during development”
Studying cortical development through the lens of human disorders
Genetic screening and modeling of human-specific neurogenesis in cerebral organoids
Untitled Seminar
Following neuronal trajectories
Malformations of the human cerebral cortex represent a major cause of developmental disabilities. To date, animal models carrying mutations of genes so far identified in human patients with brain malformations only partially recapitulate the expected phenotypes and therefore do not provide reliable models to entirely understand the molecular and cellular mechanisms responsible for these disorders. Hence, we combine the in vivo mouse model and the human brain organoids in order to better comprehend the mechanisms involved in the migration of neurons during human development and tackle the causes of neurodevelopmental disorders. Our results show that we can model human brain development and disorders using human brain organoids and contribute to open new avenues to bridge the gap of knowledge between human brain malformations and existing animal models.
Automated high-throughput generation of human neural organoids
FENS Forum 2024
A “breathing” brain model: Metabolic measurements in whole-brain organoids
FENS Forum 2024
Bulk RNA sequencing analysis to follow the neuronal maturation of AHDS organoids
FENS Forum 2024
CETN3 deficiency perturbs proliferation and differentiation of neural stem cells in the developing human cerebral organoids
FENS Forum 2024
Characterization of a new human co-culture model of endothelial cells, pericytes, and brain organoids in a microfluidic device
FENS Forum 2024
Characterization of ventral forebrain organoids derived from human induced pluripotent stem cells
FENS Forum 2024
Comprehensive functional profiling of human brain organoids
FENS Forum 2024
Cortical and spinal organoids to build the corticospinal tract
FENS Forum 2024
Decoding neuronal identity maintenance and progenitor plasticity in extended brain organoid cultures
FENS Forum 2024
Decoding retinitis pigmentosa: Unveiling PRPF31 mutation effects on human iPSC-derived retinal organoids in vitro models
FENS Forum 2024
Elevated synaptic pruning in microglia across patient-derived brain organoids
FENS Forum 2024
FOXG1 controls cellular function and tissue architecture in 2D neural rosettes and 3D cerebral organoid models of epilepsy
FENS Forum 2024
Functional analysis of spontaneous neuronal activity in cortical organoids as a model of human tauopathies
FENS Forum 2024
Generation of patient-derived cortical and spinal organoids: A promising model for studying Amyotrophic Lateral Sclerosis (ALS)
FENS Forum 2024
High-throughput neural connectivity mapping in human brain organoids
FENS Forum 2024
Hippocampal cerebral organoids as novel tool for regenerative medicine
FENS Forum 2024
Human microglia cells in Alzheimer disease-derived brain organoids: Can it be a good model?
FENS Forum 2024
Human microglia-dependent viral-mediated inflammation impairs retinal organoid development
FENS Forum 2024
Increased GABAergic neurogenesis in human cortical organoids with schizophrenia-associated SETD1A mutations
FENS Forum 2024
An innovative approach for conducting 3D electrophysiological recordings within intact brain organoids
FENS Forum 2024
Interrogating CDKL5 deficiency disorder using human iPSCs-derived cerebral organoids
FENS Forum 2024
Investigating the development of the GABAergic system using human brain organoids
FENS Forum 2024
Label-free functional analysis for the characterization of iPSC-derived neural organoid development and maturation
FENS Forum 2024
Microstructural characterization of brain organoids
FENS Forum 2024
Modelling MSA disease through the generation of brain organoids
FENS Forum 2024
Modelling Koolen-de Vries syndrome in neural organoids
FENS Forum 2024
Modelling regional specification in brain organoids using a novel mesofluidic device
FENS Forum 2024
A mosaic mTOR cortical organoid model for focal cortical dysplasia type II (FCDII)
FENS Forum 2024
Mutant huntingtin disrupts global DNA methylation in human iPSC-derived cerebral organoids
FENS Forum 2024
Next-generation electrophysiology for functional characterization of human neural organoids
FENS Forum 2024
Organoid technology: A new way to model ischemic stroke
FENS Forum 2024
LPS and pre-aggregated Abeta 1-42 lead to an increased neuroinflammatory response in cerebral organoids
FENS Forum 2024
Regulatory network of forebrain development modeled in organoids reveals key factors associated with excitatory neurons imbalance in idiopathic autism
FENS Forum 2024
The role of the ASD-associated 16p11.2 gene QPRT during differentiation of human embryonic stem cell-derived cerebral organoids
FENS Forum 2024
Single-cell CRISPR screening in cerebral organoids identifies developmental and cell type-specific defects of autism
FENS Forum 2024
Studying glioblastoma invasion in brain organoids
FENS Forum 2024
Targeting mitochondrial metabolism to restore neuronal maturation in a murine brain organoid model of Allan-Herndon-Dudley syndrome (AHDS)
FENS Forum 2024
Toward a comprehensive in vitro model of the human visual system: Three-dimensional assembloids integrating retinal and brain organoids
FENS Forum 2024
Uncovering the role of RTTN in developing brains: Insights from a human brain organoid model
FENS Forum 2024
Understanding midbrain dopaminergic cell fate acquisition using midbrain-like organoids for Parkinson’s disease cell therapy
FENS Forum 2024