Multi-modal spatiotemporal phenotyping of human retinal organoid development

Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but we lack quantitative measurements across different spatial scales and molecular modalities. Here we use a single-cell multimodal approach to reconstruct spatial protein maps over a retinal organoid time course and primary adult human retinal development. We develop a toolkit to visualize progenitor and neuron location, the spatial arrangements of extracellular and subcellular components, and global patterning in each organoid and primary tissue. In addition, we generate a single-cell transcriptome and chromatin accessibility time course dataset and infer a gene regulatory network underlying organoid development. We integrate genomic data with spatially segmented nuclei into a multi-modal atlas to explore organoid patterning and retinal ganglion cell (RGC) spatial neighborhoods, highlighting pathways involved in RGC cell death and show that mosaic genetic perturbations in retinal organoids provide insight into cell fate regulation.

Philipp Wahle

Postdoc

ETH Zürich

Philipp Wahle studied biology at the University of Bonn from 2006-2012. He finished his undergraduate studies with a diploma thesis (Msc. equivalent) with a project in human genomics, elucidating the genetics of non-syndromic cleft lip with or without cleft palate in the lab of Prof. Markus Nöthen at the Life and Brain Bonn in 2012. From 2012-213 Philipp worked as a research assistant in primate behavioral ecology at the University of Leipzig and the Max Planck Institute for Evolutionary Anthropology in the lab of Prof. Anja Widdig. During his PhD in 2014-2019 in the lab of Dr. Robert Zinzen at the Berlin Institute for Medical Systems Biology (BIMSB) he studied Drosophila nervous system development. He pioneered a spatially single-cell resolved transcriptome atlas and his PhD was awarded the MDC PhD prize.
He received an EMBO LTF fellowship to pursue a postdoc at the Institue for Molecular and Medical Ophthalmology and the Eidgenössisch Technische Hochschule Zürich (ETH Zürich, D-BSSE, Basel) in the labs of Prof. J. Grayson Camp and Prof. Barbara Treutlein. He developed a high-content imaging screen and computational tools to develop a retinal organoid expression atlas. He combined highly multiplexed highly resolved protein localization patterns with RNA expression and chromatin accessibility in a retinal organoid developmental time course. He is now applying the technology developed to a number of other projects including microglia co-culture systems, human fetal brains, and human cerebral organoids.

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Multi-modal spatiotemporal phenotyping of human retinal organoid development
Open to view video.  |   Closed captions available
Open to view video.  |   Closed captions available Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but we lack quantitative measurements across different spatial scales and molecular modalities. Here we use a single-cell multimodal approach to reconstruct spatial protein maps over a retinal organoid time course and primary adult human retinal development. We develop a toolkit to visualize progenitor and neuron location, the spatial arrangements of extracellular and subcellular components, and global patterning in each organoid and primary tissue. In addition, we generate a single-cell transcriptome and chromatin accessibility time course dataset and infer a gene regulatory network underlying organoid development. We integrate genomic data with spatially segmented nuclei into a multi-modal atlas to explore organoid patterning and retinal ganglion cell (RGC) spatial neighborhoods, highlighting pathways involved in RGC cell death and show that mosaic genetic perturbations in retinal organoids provide insight into cell fate regulation.
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