CIRCUITS: IPS Cells and the Human Brain

There is no doubt that iPS cells derived from peripheral cells have enormous promise for personalized medicine, biomarker development, individualized treatment strategies and fundamental understanding of neurodegenerative disease. The ability to differentiate fibroblasts, for example, into relevant central nervous system cells, including cells that appear to be neurons and glia, is fascinating new science. Yet the connection between the cells that are in the dish, and the actual neurons and glia in the brain of the same individual, is truly unknown. A critical assumption of the field is that iPS cell-derived neurons and glia reflect the actual biology of the mature cells that have evolved in the brain, and then matured over the course of the person’s lifetime. Importantly, this assumption has never been tested.

We now propose to develop a resource to support the CIRCUITS consortium to overcome this critical and fundamental problem. Through our well-established neurodegenerative disease brain bank and tissue repository, we now have institutional review board approval to obtain fibroblasts at autopsy, and grow them and convert to iPS lines for omics discovery, while at the same time having brain tissue for 1) definitive diagnosis; 2) newly developed homogenization/cell separation technologies to provide enriched populations of microglia, astrocytes, endothelial cells and neurons. We will be able to provide the matched fibroblast and isolated brain cell samples to investigators in the CIRCUITS consortium for omics analyses, to understand in what ways iPS cells resemble, and in what ways iPS cells differ, from the cell populations that are intended to model; provide underlying deeply phenotyped data, both neuropathologically and clinically, to CIRCUITS collaborators to provide a context for omics analyses; and explore new methods to culture the isolated cell types from post-mortem brain in culture to have an in vitro paradigm to test interventions directly in adult, mature brain cells.

Recent studies demonstrate that skin cells can be converted into induced pluripotent stem cells (iPSC). These iPSC are derived from skin or blood cells that have been reprogrammed back into an embryonic-like state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes. Skin cells and iPSC both can be grown in the laboratory and converted into brain cells like neurons and microglia. This project will generate skin cells that can be converted into iPS cells or neurons and microglia in order to determine the extent to which the cells generated in the laboratory resemble the actual brain cells they are intended to model.