Human Astrocytes Model Derived from Induced Pluripotent Stem Cells

Abstract

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.

Generation of star-shaped human induced astrocytes with a mature inflammatory phenotype for CNS disease modeling

“…Over the past years, there has been a plethora of astrocytic differentiation protocols, some more elaborate and time-consuming than others, spanning over many months or sorting steps(Holmqvist et al ., 2015; Santos et al ., 2017; Leventoux et al ., 2020). Our differentiation strategy relies on creating an astrocytogenic milieu that brings forth astrocytic traits in only 28 days.…”

“…Notch signaling has been shown to increase GLT-1 expression in mice (Lee et al ., 2017), and the same has been shown for bFGF (Savchenko et al ., 2019). Other groups have shown EAAT2 expression in iPS-derived astrocytes (Roybon et al ., 2013; Shaltouki et al ., 2013; Leventoux et al ., 2020), and here we report on an astrocytic model that shows specific EAAT2 expression and functionality.…”

Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases

“…To address this issue, induced pluripotent stem cell (iPSC) technology appear to be a powerful tool. We recently showed that the astrocyte–neuron lactate shuttle is also feasible in human astrocytes and neurons using human iPSC derived astroglia and neurons [ 82 ]. Likewise, human iPSC-derived microglia and astroglia would enable more reliable information regarding their possible interactions to be obtained.…”

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

“…Modifying neural cell culture protocols to increase maturation in vitro has, however, yielded some degree of success. Co-culture of neurons with astrocytes has long been shown to increase neurite outgrowth and activity, and this approach is now yielding more physiologically relevant iPSC-derived neuronal cell disease models (Odawara et al, 2014 ; Kuijlaars et al, 2016 ; di Domenico et al, 2019 ; Enright et al, 2020 ; Leventoux et al, 2020 ). Cell culture media formulated to mimic human cerebral spinal fluid (Bardy et al, 2015 ) increases neuron maturation and generates neurons which become active at a much earlier stage in culture.…”