Protein expression profiles in brain organoids are more similar to those in human brain parenchyma than in mouse brain parenchyma

Summary Human brain organoids are emerging as relevant models for the study of human brain health and disease. However, it has not been shown whether human brain organoids exhibit a proteoform profile similar to the human brain. Herein, we demonstrate that unguided brain organoids exhibit minimal batch-to-batch variability in cell composition and metabolism when generated from induced pluripotent stem cells (iPSCs) derived from male-female siblings. We then show that profiles of select proteins in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples. Brain organoids derived from sibling iPSCs do not exhibit any sex differences in protein proportions. By benchmarking human brain organoid proteoforms against human parenchymal tissue, we establish the foundation for future studies that could investigate, for example, how well brain organoids can model any of the known sex-dependent differences in cellular function, including responses of drug-receptor interactions. Highlights Brain organoids (BOs) display protein banding similar to human parenchymal lysates Protein banding differs between mouse and human brain parenchyma lysates Sibling-derived BOs have similar cell composition and metabolism at day 90 Sibling-derived BOs exhibit similar protein banding at day 90