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Traumatic Injury-Induced Cell Responses in Human Cortical Organoids 10.17863/CAM.93210 Limegrover, Colleen Lakatos, Andras Traumatic brain injury (TBI) impacts millions of individuals worldwide each year, which often leads to permanent disabilities and emerges as an important risk factor for neurodegenerative diseases. This is driven by secondary injury cascades of cellular toxicity, inflammation, and aggregation of toxic proteins. Although animal models and reductionist human cell culture systems provided important mechanistic insights, there is no available therapy to prevent pathological progression, which warrants the need for more sophisticated human models. Here, I developed a 3D human stem cell-derived cerebral organoid slice culture that recapitulates cortical cell diversity and mimics aspects of human traumatic brain injury. This accessible multicellular model allows more precise observations on human CNS-specific propagation of cellular insults. Using single-cell transcriptomic and in vitro validation approaches, I demonstrate typical injury related primary and secondary pathologies. In addition, I show that in the lack of innate immune cells, glial responses are subtle without significant upregulation of reactive and inflammatory markers 3 days post-injury at 150 days in vitro (DIV). When human stem cell-derived macrophages are pre-seeded prior to injury, the weight-drop impact results in microglia activation characterized by microglia ramification and expression of complement C3, CD68 and NF-kB. Surprisingly, this impedes rather than increases the proliferation of glial progenitors and astrocytes in 150 DIV cortical organoids. Our results highlight potential differences in fetal astroglia-microglia interactions to that found for the adult brain and provide a unique platform for cell interaction-based studies with broad relevance to TBI pathogenesis and therapeutics. University of Cambridge 2022-09-01 Thesis Doctoral Doctor of Philosophy (PhD) eng Bill and Melinda Gates Foundation https://www.repository.cam.ac.uk/handle/1810/345788 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c0e34029-c109-463b-b425-5d41fd97f07b/download a09814bfe11c0f9abaf4bbea8da62ea2 https://www.rioxx.net/licenses/all-rights-reserved/ Organoid traumatic brain injury model development microglia astrocytes