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

ABSTRACT: Astrocytes 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.

SUBMITTER: Hedegaard A

PROVIDER: S-EPMC7363746 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance. We present here a method for detecting analytes secreted from single human induced pluripotent stem cell (iPSC)-derived neural cells and have applied the method to measure amyloid ? (A?) and soluble amyloid precursor protein-alpha (sAPP?), analytes central to Alzheimer's disease pathogenesis. Through these studies, we have uncovered the dynamic range of secretion profiles of these analytes from single iPSC-derived neuronal and glial cells and have molecularly characterized subpopulations of these cells through immunostaining and gene expression analyses. In examining A? and sAPP? secretion from single cells, we were able to identify previously unappreciated complexities in the biology of APP cleavage that could not otherwise have been found by studying averaged responses over pools of cells. This technique can be readily adapted to the detection of other analytes secreted by neural cells, which would have the potential to open new perspectives into human CNS development and dysfunction.We have established a technology that, for the first time, detects secreted analytes from single human neurons and astrocytes. We examine secretion of the Alzheimer's disease-relevant factors amyloid ? (A?) and soluble amyloid precursor protein-alpha (sAPP?) and present novel findings that could not have been observed without a single-cell analytical platform. First, we identify a previously unappreciated subpopulation that secretes high levels of A? in the absence of detectable sAPP?. Further, we show that multiple cell types secrete high levels of A? and sAPP?, but cells expressing GABAergic neuronal markers are overrepresented. Finally, we show that astrocytes are competent to secrete high levels of A? and therefore may be a significant contributor to A? accumulation in the brain.

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

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