Modeling Cerebral Innate Immunity with Human iPS cells

The immune privilege of the human brain has been challenged over the years. It is now recognized that there is far more communication between the periphery and the central nervous system (CNS). Microglia, the resident immune cells of the brain, are poised to be a primary relay for such a dialogue. Genes expressed solely in microglia keep topping the lists of genome wide-associations for neurological and psychiatric disorders. Microglia emerge as embryonic macrophages from the yolk sac. They are a natural "transplant", as they home in on their target organ: they are the first cells to migrate among neural stem cells, before blood begins circulating. They eventually tile the tissue performing several tasks in the maintenance and repair of the developing brain. In absence of insult, no adult peripheral macrophage replaces them. Like all cells of the myeloid lineages, they can internalize and harbor viruses and other pathogens. Human pluripotent stem cells (hPSCs) are uniquely suited to study microglial differentiation. We developed a novel culture system that replicates their developmental trajectory and residency. Eventually, we embed these cells in organotypic tissue containing all mature cell types of the brain parenchyma, exposing immature microglia to a cerebral microenvironment. They adopt most of the molecular signatures of their primary counterparts, and can continue to mature, performing the expected surveying tasks of quiescent microglia, responding to cellular injury, secreting cytokines or phagocytizing synaptic termini. Given their travels between yolk sac and nervous system, we asked whether microglia may play a role in seeding teratogenic viral infections such as Zika. In parallel, we worked to identify, through a genome-wide CRISPR screen, determinants of lethal Zika infection in human neural progenitors.