Retrograde interferon-gamma signaling induces major histocompatibility class I expression in human-induced pluripotent stem cell-derived neurons
Abstract
Injury-associated axon-intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFNγ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen-specific CD8+T cells. We sought to determine whether the same is true in human neurons. A novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast-derived induced pluripotent stem cell (iPSC)-derived neuron-enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFNγfor 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT-PCR and immunofluorescence. Human iPSC-derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFNγresulted in upregulation of MHC class I and antigen...Continue Reading
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