SOX9-induced Generation of Functional Astrocytes Supporting Neuronal Maturation in an All-human System

• Published in: Stem cell reviews and reports 2021-10, Vol.17 (5), p.1855-1873
• Main Authors: Neyrinck, Katrien, Van Den Daele, Johanna, Vervliet, Tim, De Smedt, Jonathan, Wierda, Keimpe, Nijs, Melissa, Vanbokhoven, Tom, D’hondt, Astrid, Planque, Mélanie, Fendt, Sarah-Maria, Shih, Pei-Yu, Seibt, Frederik, Almenar, Juan Pita, Kreir, Mohamed, Kumar, Devesh, Broccoli, Vania, Bultynck, Geert, Ebneth, Andreas, Cabrera-Socorro, Alfredo, Verfaillie, Catherine
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer's disease; Animals; Astrocytes; Astrocytes - cytology; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedical research; Brain research; Calcium influx; Cell Biology; Cytokines; Drug development; Gene expression; Genomes; Growth factors; Humans; Induced Pluripotent Stem Cells - cytology; Kinases; Laboratories; Life Sciences; Maturation; Medical research; Metabolism; Mice; Nervous system; Neural stem cells; Neural Stem Cells - physiology; Neurogenesis - physiology; Neurological diseases; Neurons - cytology; Neurosciences; Plasmids; Pluripotency; Progenitor cells; R&D; Regenerative Medicine/Tissue Engineering; Research & development; Sox9 protein; SOX9 Transcription Factor - metabolism; Stem Cells
• ISSN: 2629-3269; 2629-3277
• DOI: 10.1007/s12015-021-10179-x

Astrocytes, the main supportive cell type of the brain, show functional impairments upon ageing and in a broad spectrum of neurological disorders. Limited access to human astroglia for pre-clinical studies has been a major bottleneck delaying our understanding of their role in brain health and disease. We demonstrate here that functionally mature human astrocytes can be generated by SOX9 overexpression for 6 days in pluripotent stem cell (PSC)-derived neural progenitor cells. Inducible (i)SOX9-astrocytes display functional properties comparable to primary human astrocytes comprising glutamate uptake, induced calcium responses and cytokine/growth factor secretion. Importantly, electrophysiological properties of iNGN2-neurons co-cultured with iSOX9-astrocytes are indistinguishable from gold-standard murine primary cultures. The high yield, fast timing and the possibility to cryopreserve iSOX9-astrocytes without losing functional properties makes them suitable for scaled-up production for high-throughput analyses. Our findings represent a step forward to an all-human iPSC-derived neural model for drug development in neuroscience and towards the reduction of animal use in biomedical research. Graphical Abstract