Pro-maturational Effects of Human iPSC-Derived Cortical Astrocytes upon iPSC-Derived Cortical Neurons.

Anne Hedegaard,Colin J Akerman,Emma S Whiteley,Jimena Monzón-Sandoval,Sarah E Newey,Caleb Webber

doi:10.1016/j.stemcr.2020.05.003

Anne Hedegaard, Colin J Akerman + Show 4 more

Open Access

https://doi.org/10.1016/j.stemcr.2020.05.003

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Abstract

SummaryAstrocytes influence neuronal maturation and function by providing trophic support, regulating the extracellular environment, and modulating signaling at synapses. The emergence of induced pluripotent stem cell (iPSC) technology offers a human system with which to validate and re-evaluate insights from animal studies. Here, we set out to examine interactions between human astrocytes and neurons derived from a common cortical progenitor pool, thereby recapitulating aspects of in vivo cortical development. We show that the cortical iPSC-derived astrocytes exhibit many of the molecular and functional hallmarks of astrocytes. Furthermore, optogenetic and electrophysiological co-culture experiments reveal that the iPSC-astrocytes can actively modulate ongoing synaptic transmission and exert pro-maturational effects upon developing networks of iPSC-derived cortical neurons. Finally, transcriptomic analyses implicate synapse-associated extracellular signaling in the astrocytes' pro-maturational effects upon the iPSC-derived neurons. This work helps lay the foundation for future investigations into astrocyte-to-neuron interactions in human health and disease.

Highlights

Most of our knowledge regarding astrocyte-neuron interactions has been gained from animal models, which have been important in advancing understanding at a molecular and cellular level
Deriving Human Astrocytes and Neurons from a Common Cortical Progenitor Pool Since cortical neurons and astrocytes can originate from the same progenitors in vivo (Rowitch and Kriegstein, 2010), we set out to generate induced pluripotent stem cell (iPSC)-derived neurons and astrocytes from a common cortical progenitor pool
After a further 10–20 days, all cell lines were enriched for putative astrocytes

Summary

Introduction

Most of our knowledge regarding astrocyte-neuron interactions has been gained from animal models, which have been important in advancing understanding at a molecular and cellular level. IPSC differentiation protocols have generally targeted the gliogenic JAK-STAT pathway via manipulations of culture media This strategy enables re-capitulation of stages of in vivo development leading to astrocyte production over different timescales (Krencik et al, 2011; Serio et al, 2013; Shaltouki et al, 2013; Sloan et al, 2017), and with the potential for regional patterning during the preceding neurogenic stage (Liu and Zhang, 2011; Roybon et al, 2013). To our knowledge, rapid astrocyte-mediated modulation of ongoing synaptic transmission has not previously been demonstrated in an iPSC-derived human co-culture

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