Single-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids

E-print/Working paper (2019)

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an ... [more ▼]

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery. [less ▲]

Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

in Stem Cell Reports (2019)

Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation

in Frontiers in Neuroscience (2019)

Automated microfluidic cell culture of stem cell derived dopaminergic neurons

in Scientific Reports (2019)

Non-proteolytic ubiquitination of OTULIN regulates NF-κB signaling pathway

in Journal of Molecular Cell Biology (2019)

3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

in Advanced Science (2018)

Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific neurons, derived from induced pluripotent stem ... [more ▼]

Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific neurons, derived from induced pluripotent stem cells carrying the LRRK2‐G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease‐relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High‐content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2‐G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2‐G2019S‐dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2‐G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development. [less ▲]

In vivo Phenotyping of Human Parkinson’s Disease-Specific Stem Cells Carrying the LRRK2-G2019S Mutation Reveals Increased a-Synuclein Levels but Absence of Spreading

in Opera Medica et Physiologica (2018)

Advanced Good Cell Culture Practice for human primary, stem cell-derived and organoid models as well as microphysiological systems

in ALTEX : Alternativen zu Tierexperimenten (2018)

Is Parkinson’s disease a neurodevelopmental disorder and will brain organoids help us to understand it?

in Stem Cells and Development (2018)

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

in Proceedings of the National Academy of Sciences of the United States of America (2017)