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In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids

ABSTRACT: In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids

PROVIDER: PRJNA907795 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22505759_1.fastq.gz	Fastqsanger.gz
	SRR22505759_2.fastq.gz	Fastqsanger.gz
	SRR22505760_1.fastq.gz	Fastqsanger.gz
	SRR22505760_2.fastq.gz	Fastqsanger.gz
	SRR22505761_1.fastq.gz	Fastqsanger.gz

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In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [Smartseq]

Project description:Dopaminergic neurons located in the ventral Midbrain (vMid) innervate the striatum and cortex and are involved in movement control and reward-related cognition. Degeneration of dopaminergic neurons causes Parkinson’s disease (PD), while their over-activation is implicated in addiction. Thus, modeling the dopaminergic system is of broad relevance for disease research and drug discovery, although limited availability of patient material and inherent differences in animal model systems are restricting the study of distinctive human specific features such as development and neurodegeneration. Here, we show that spatially arranged assembloids can recapitulate dopaminergic innervation of striatum and cortex and offer methods for their use in cell replacement therapy and addiction research. We describe improved protocols for growing vMid, striatal and cortical organoids and use custom embedding molds to fuse them in a linear manner. Linear assembloids form functional long-range dopaminergic connections with striatal and cortical tissues that can release dopamine. We demonstrate that vMid grafts derived from hPSCs for cell replacement therapy of PD can integrate into the tissue and structurally mature. Additionally, we demonstrate that our model can be used to study dopaminergic circuit perturbations in the example of chronic cocaine treatment which causes morphological, functional and transcriptional changes that remained altered even after drug withdrawal. Our method opens new avenues for dopaminergic cell replacement therapy and the analysis of drugs affecting the dopaminergic system, directly in a human system.

2023-09-20 | GSE219246 | GEO

In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [scRNAseq]

2023-09-20 | GSE219245 | GEO

In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [Smartseq]

Project description:In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [Smartseq]

| PRJNA907800 | ENA

In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [scRNAseq]

Project description:In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [scRNAseq]

| PRJNA907801 | ENA

Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids [scRNA-Seq]

Project description:Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

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Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids [RNA-Seq]

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Identifying secreted biomarkers of dopaminergic ventral midbrain progenitor cells

Project description:Ventral midbrain (VM) dopaminergic progenitor cells derived from human pluripotent stem cells have the potential to replace endogenously lost dopamine neurons and are currently in preclinical and clinical development for treatment of Parkinson’s Disease (PD). However, one main challenge in the quality control of the cells is that rostral and caudal VM progenitors are extremely similar transcriptionally though only the caudal VM cells give rise to dopaminergic neurons with functionality in PD. Therefore, it is critical to develop assays which can rapidly and reliably discriminate rostral from caudal VM cells during clinical manufacturing. Here, we applied shotgun proteomics to search for novel secreted biomarkers specific for caudal VM progenitors compared to rostral VM progenitors and validated key hits by ELISA. From this, we identified novel secreted markers (CPE, LGI1 and PDGFC) significantly enriched in caudal versus rostral VM progenitor cultures, whereas the markers CNTN2 and CORIN were significantly enriched in rostral VM cultures. With this data, we suggest and test in clinical grade samples a panel of coupled ELISA assays that can be applied as a quality control tool for assessing the correct patterning of cells during clinical manufacturing.

2023-12-13 | PXD039510 | Pride

In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids.

Project description:Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson's disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson's disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain-striatum-cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.

| S-EPMC10703680 | biostudies-literature

Translating ribosome affinity purification analysis of dopaminergic neurons of the mouse ventral midbrain with age and alpha-synuclein overexpression.

Project description:To investigate the cell type-specific expression features of dopaminergic neurons in ventral midbrain, we generated DAT-TRAP mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of samples collected from 3- and 18-month old mice. OVX were also bred to overexpress human alpha-synuclein. Short and long-read sequencing were performed.

2023-10-01 | GSE215276 | GEO

RNA-SEQ profiling of dopaminergic neurons from the substantia nigra pars compacta and ventral tegmental area regions of the mouse mid-brain

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