2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size.

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Otani, Tomoki 
Marchetto, Maria C 
Gage, Fred H 
Simons, Benjamin D 
Livesey, Frederick J 

Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.

Animals, Cell Cycle, Cell Differentiation, Cells, Cultured, Cerebral Cortex, Humans, Models, Biological, Neurons, Organ Size, Organoids, Pluripotent Stem Cells, Primates, Species Specificity
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Cell Stem Cell
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Elsevier BV
Wellcome Trust (098357/Z/12/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/L023784/2)
Medical Research Council (MR/L023784/1)
T.O. was supported by the Wellcome Trust PhD Programme in Developmental Biology at the University of Cambridge. F.J.L. and B.D.S. are Wellcome Trust Investigators. This research was supported by core funding to the Gurdon Institute by the Wellcome Trust and Cancer Research UK. F.H.G. was supported by the Helmsley, Mathers, and JPB Foundations.