Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models

Abstract

Summary: In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology. : Human studies can typically not be used to understand cellular functions of the brain. Astrocytes, important for neuronal circuit regulation and support, lack cellular model characterization and biological translation. Falk, Herland, and colleagues report striking differences in astrocyte models. A pilot screen of Alzheimer's disease-related drugs demonstrates dependence between compound hit finding and astrocytic model biology. Keywords: astrocytes, induced pluripotent stem cells, cell differentiation, glutamate plasma membrane transport proteins, neuroinflammation, calcium signaling, apolipoproteins E, high-throughput screening assays, neurodegenerative diseases, drug discovery