MIF modulates impaired astrocyte distribution in schizophrenia cortical spheroids

Neuroinflammation and astrocyte dysfunction are associated with schizophrenia. To elucidate the molecular mechanisms involved, we generated induced pluripotent stem cells from 14 schizophrenia patients and 14 healthy controls and differentiated them to human cortical spheroids. Transcriptional profiling revealed overexpression of cilia-related genes in schizophrenia spheroids which was mainly driven by astrocytes. We identified baseline abnormal astrocyte distribution in schizophrenia and show that it is triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), primarily secreted by neurons. While treatment with the MIF antagonist ISO-1 attenuated abnormal astrocyte distribution in schizophrenia spheroids and reduced pro-inflammatory cytokines secretion, MIF gene knockout with CRISPR-Cas9 exacerbated astrocyte and cytokines dysregulation in schizophrenia cultures, suggesting that both extremes of elevated and absent MIF lead to impaired astrocyte distribution and that a minimum expression of MIF is required for optimal cell function. Taken together, our results point to a MIF-induced regulation of cortical astroglia in schizophrenia and highlight MIF antagonists as potential novel treatment strategies.