An all human iPSC derived model to study the role of microglia in neurodegeneration

The hypothesis of this proposal is that microglia play both cell-autonomous and reactive roles in neurodegeneration causing dementia. Although animal models have provided important information regarding the mechanisms underlying the dementia development, they fall short in that they do not fully recapitulate the human disease. With the advent of iPSC technology combined with advanced genome engineering and (co)culture systems, we now have the tools available to create not only human neurons, but also microglia-like cells that are though to either directly play a causative role in neurodegeneration; or react to degenerating neurons, further aggravating neuronal loss. We here propose to create microglia from human iPSC using a combination of transcription factor guided differentiation, and cocultures in the presence of iPSC derived early cortical progenitors that mimic the niche wherein microglia reside, to create microglia that very closely resemble their in vivo counterparts. This should then allow investigators, including ourselves, to start addressing the question what the contribution of microglia is to neurodegeneration, starting from cells that very closely resemble the in vivo cell counterpart.