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Developing Human Pluripotent Stem Cell-Based Cerebral Organoids with a Controllable Microglia Ratio for Modeling Brain Development and Pathology

By Ranjie Xu, Andrew J. Boreland, Xiaoxi Li, Caroline Erickson, Mengmeng Jin, Colm Atkins, Zhiping Pang, Brian P Daniels, Peng Jiang

Posted 12 Oct 2020
bioRxiv DOI: 10.1101/2020.10.09.331710

Microglia, as the brain-resident macrophages, play critical roles in brain development, homeostasis, and disease. Microglia in animal models cannot accurately model the properties of human microglia, because there are due to notable transcriptomic and functional differences between human and other animal microglia at transcriptomic and functional levels. Efficient generation of microglia from human pluripotent stem cells (hPSCs) provides unprecedented opportunities to study the function and behavior of human microglia. Particularly, incorporating hPSCs-derived microglia into brain organoids facilitates their development in a 3-dimensional context, mimicking the brain environment. However, an optimized method that integrates an appropriate amount of microglia into brain organoids at a proper time point, similar to what is seen in vivo, is still needed. Here, we report the development of a new brain region-specific, microglia-containing organoid model by co-culturing hPSCs-derived primitive neural progenitor cells (pNPCs) and primitive macrophage progenitors (PMPs). In these organoids, hPSCs-derived pNPCs and PMPs interact with each other and develop into functional neurons, astroglia, and microglia, respectively. Importantly, the numbers of human microglia population in the organoids can be controlled, resulting in a cell type at a ratio similar to that seen in the human brain. Importantly, uUsing super-resolution microscopy, we demonstrate that these human microglia are able to phagocytize neural progenitor cells (NPCs) and dead cells, as well as to prune synapses at different developmental stages of the organoids. Furthermore, these human microglia respond to Zika virus infection in of the organoids, as indicated by exhibiting amoeboid-like morphology, an increased expression of gene transcripts encoding inflammatory cytokines, and excessive pruning of synaptic materials. ThusTogether, our findings establish a new microglia-containing brain organoid model that will serve to study human microglial function in a variety of neurological disorders.

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