Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, Astrocytes, Pluripotent stem cells, Differentiation protocol, Genome engineering, All-human co-culture system, INDUCED CALCIUM-RELEASE, HOMEOSTASIS, MECHANISMS, PROGENITOR, SOX9, Animals, Humans, Induced Pluripotent Stem Cells, Mice, Neural Stem Cells, Neurogenesis, Neurons, SOX9 Transcription Factor, 12ZG121N#55744113, AKUL/19/34#55685676, G0B5819N#54971384, 06 Biological Sciences, 10 Technology, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences

Abstract:

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.