Novel Three-Dimensional Astrocyte-Containing Organoids Recapitulate Key Aspects of Human Neurodegenerative Disease
Huinan Li 1, Kyounghee Seo1, Michael Ward2 and Erik Ullian1 1Department of Ophthamalogy, School of Medicine, University of California San Francisco, 10 Koret Way, San Francisco, CA 94143; 2National Institute of Health, NINDS, Inherited Neurodegenerative disease Unit, Porter Neuroscience Research Center 35 Convent Drive, Bethesda MD 20892-3704
Astrocytes are the single most abundant cell type in the human brain, and an increasing number of neurological disorders have been associated with astrocyte pathology. Importantly human astrocytes are unique based on both morphology and gene expression. In our lab, we have developed new co-culture systems utilizing three-dimensional (3D) astrocyte-containing organoids containing induced pluripotent stem cell-derived astroglia combined with either neural stem cell-derived or directly induced neurons and microglia. Our 3D Asteroid system successfully reproduces structurally complex astrocytes that retain the unique morphological and gene expression characteristics of adult human brain. Therefore, this approach allows for detailed studies of specific human astrocyte gene function in disease modeling and drug screening. We are now applying this approach to a stem cell model of frontotemporal lobar dementia (FTLD). Human astrocyte-containing organoids revealed cell autonomous and non-autonomous requirements for astrocytes in reproducing key features of human FTD pathology. We are extending this work to examine how astrocytes impact lysosomal function and cellular stress in neurons using our organoid system, along with CRISPR, biochemistry, and machine-learning imaging approaches. Our 3D Asteroid model systems are reproducible and scalable tools to more accurately model unique human neuron-glial functional properties in neurodegenerative disease while being easily accessible for manipulations and observations. (Support: Paul Allen Family Foundation, TMMS).