We are actively developing approaches for efficient replacement of endogenous microglia with transplanted progenitors. Our work has shown that even blood-derived progenitors can enter the brain and replace microglia, if host microglia are depleted and prevented from repopulating for an extended period. We are now developing translatable strategies to enhance this process by giving transplanted cells a competitive advantage.
A second objective has been to identify progenitors that efficiently engraft the brain and develop into bona fide microglia. We demonstrated that in contrast to adult bone marrow-derived progenitors, fetal monocytes have the intrinsic potential to develop into microglia that closely resemble their endogenous counterparts. Building on this, we generated induced pluripotent stem cell (iPSC)-derived progenitors that efficiently engraft the brain and closely resemble native microglia. These cells adopt normal microglial morphology and gene expression, can be genetically engineered, and show self-renewal. We are currently testing their therapeutic potential in neurodegenerative disease models, and have created engineered lines that overexpress therapeutically relevant proteins. Finally, we have developed a novel platform that combines microglia replacement with advanced genetic screening directly in the brain. This approach enables screening of gene function in microglia within their native environment, providing a powerful way to uncover the gene networks that regulate their survival, renewal, and activation. Together, these advances establish new methodologies for studying microglia in health and disease and lay the foundation for future microglia-based therapies.
