Multiple Sclerosis-Related Cell Interactions Informed by Genetic Screening Approach

An international team reporting in Science presents multiple sclerosis-related central nervous cell interactions identified with the help of a forward genetic screening approach. The "systematic perturbation of encapsulated associated cells followed by sequencing," or SPEAC-seq, method relies on CRISPR-Cas9 gene editing-based genetic perturbation, droplet-based cell co-culturing, and fluorescence-activated droplet sorting in a microfluidic system, the researchers say, adding that is then followed by sequencing to systematically untangle communication between cells. After applying their SPEAC-seq strategy to explore typical communication between microglia and astrocyte cells harvested from mouse central nervous system samples, where they found microglia factors such as amphiregulin that rein in proinflammatory signaling by astrocytes, they went on to assess samples from a mouse preclinical model of MS called experimental autoimmune encephalomyelitis (EAE) as well as MS patient samples. Together, the latter experiments point to suppression of inflammatory astrocyte responses by amphiregulin expression and interleukin 33 signaling in ST2-positive microglia cells (IL-33-ST2). "Using SPEAC-seq, we identified a regulatory negative feedback loop that is driven by microglia-astrocyte interactions … that limits astrocyte NF-kappa-B-driven proinflammatory responses that promote CNS pathology in EAE and, potentially, MS," the authors write, adding that the results more broadly "point to the importance of reactivation of development programs in neurologic diseases."