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

Hedegaard, Anne; Monzón‐Sandoval, Jimena; Newey, Sarah E.; Whiteley, Emma; Webber, Caleb; Akerman, Colin J.

doi:10.1016/j.stemcr.2020.05.003

Cited by 54 publications

(43 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the neuronal marker TUBB3 was significantly downregulated from A0-step to A4-step ( Figure S1C ). Thus, this final-passages stage constitutes an improvement of the present method compared with other protocols [ 16 , 18 ] for the enrichment of iPSCs-derived astrocytes. On the other hand, this purity might also interfere with the functionality of astrocytes.…”

Section: Discussionmentioning

confidence: 95%

“…Astrocytes also regulate neuronal synapses by promoting synaptogenesis [ 11 ] or by modulating synaptic transmission through the transport of various amino acids, such as glutamate [ 12 , 13 ]. While previous reports have relied mainly on transcriptome and protein expression analyses [ 14 ] or calcium imaging studies [ 15 , 16 ] to characterize iPSC-astrocytes derived lines, only a few groups have performed co-culture with neurons [ 17 , 18 ] or investigated their glucose metabolism [ 19 , 20 ] and to the best of our knowledge, none has conducted all these analyses concurrently.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human Astrocytes Model Derived from Induced Pluripotent Stem Cells

Leventoux

Morimoto

Imaizumi

et al. 2020

Cells

View full text Add to dashboard Cite

Induced pluripotent stem cell (iPSC)-based disease modeling has a great potential for uncovering the mechanisms of pathogenesis, especially in the case of neurodegenerative diseases where disease-susceptible cells can usually not be obtained from patients. So far, the iPSC-based modeling of neurodegenerative diseases has mainly focused on neurons because the protocols for generating astrocytes from iPSCs have not been fully established. The growing evidence of astrocytes’ contribution to neurodegenerative diseases has underscored the lack of iPSC-derived astrocyte models. In the present study, we established a protocol to efficiently generate iPSC-derived astrocytes (iPasts), which were further characterized by RNA and protein expression profiles as well as functional assays. iPasts exhibited calcium dynamics and glutamate uptake activity comparable to human primary astrocytes. Moreover, when co-cultured with neurons, iPasts enhanced neuronal synaptic maturation. Our protocol can be used for modeling astrocyte-related disease phenotypes in vitro and further exploring the contribution of astrocytes to neurodegenerative diseases.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Human Astrocytes Model Derived from Induced Pluripotent Stem Cells

Leventoux

Morimoto

Imaizumi

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Therefore, we assessed the neurophysiological properties of iPSC-derived neurons when co-cultured with iSOX9-astrocytes. Until now, variable effects of PSCderived astrocytes on neuronal maturation have been described via patch clamp [20,22,61,62]. For our study, neurons generated by the inducible overexpression of NGN2 from the AAVS1 locus in PSCs [10,12] were used.…”

Section: Discussionmentioning

confidence: 99%

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

Neyrinck

Daele

Vervliet

et al. 2021

Stem Cell Rev and Rep

View full text Add to dashboard Cite

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

show abstract

“…On the other hand, in vitro methodologies to study the effects of neuronal activity use either pharmacological agents, such as bicuculline [ 22 ], or ChR2 using pan-neuronal promoters [ 51 ]. Dissecting specific effects of each type of neuronal signaling would require systematic co-culture with each neuronal subtype that would require differential culture conditions.…”

Section: Discussionmentioning

confidence: 99%

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

Sardar

Lozzi

Woo

et al. 2021

IJMS

View full text Add to dashboard Cite

Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties associated with dissecting neuron- versus astrocyte-specific effects. Here, we use an in vitro system of stem cell-derived astrocytes to identify gene expression profiles in astrocytes that are influenced by neurons and regulate astrocyte development. Furthermore, we show that neurotransmitters and neuromodulators induce distinct transcriptomic and chromatin accessibility changes in astrocytes that are unique to each of these neuroactive compounds. These findings are highlighted by the observation that noradrenaline has a more profound effect on transcriptional profiles of astrocytes compared to glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and serotonin. This is demonstrated through enhanced noradrenaline-induced transcriptomic and chromatin accessibility changes in vitro and through enhanced calcium signaling in vivo. Taken together, our study reveals distinct transcriptomic and chromatin architecture signatures in astrocytes in response to neuronal-derived neuroactive compounds. Since astrocyte function is affected in all neurological disorders, this study provides a new entry point for exploring genetic mechanisms of astrocyte–neuron communication that may be dysregulated in disease.

show abstract

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

Cited by 54 publications

References 56 publications

Human Astrocytes Model Derived from Induced Pluripotent Stem Cells

Human Astrocytes Model Derived from Induced Pluripotent Stem Cells

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

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

Contact Info

Product

Resources

About