We have established a platform for querying astrocyte-specific contributions to disease predisposition in hiPSC-based models. hiPSC-astrocytes closely resemble primary human fetal astrocytes, purified adult brain astrocytes (Zhang et al., 2016), and brain tissue homogenate (Miller et al., 2014) (Figures 2 and 3A). Although the transcriptional profile of our hiPSC-astrocytes most closely resembles a quiescent state (Figure 3B), hiPSC-astrocytes secrete various cytokines and chemokines in response to neuroinflammatory stimuli (Figures 3C and 3D). hiPSC-astrocytes displayed phagocytic capacity (Figure 4A) and enhanced the phagocytic function of microglia in a co-culture assay (Figure 4C). They also showed spontaneous calcium transient activity and responses to glutamate stimulus (Figure 5). Moreover, because nearly pure populations of excitatory neurons and astrocytes from the same individual, hiPSC clone, and even NPC batch can now be compared, our protocol may reduce experimental variation in studies of the cell-autonomous and non-cell-autonomous factors underlying disease predisposition.
