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Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells
Chen Chen, … , Woo-Yang Kim, Peng Jiang
Chen Chen, … , Woo-Yang Kim, Peng Jiang
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e88632. https://doi.org/10.1172/jci.insight.88632.
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Research Article Neuroscience Stem cells

Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells

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Abstract

The creation of a humanized chimeric mouse nervous system permits the study of human neural development and disease pathogenesis using human cells in vivo. Humanized glial chimeric mice with the brain and spinal cord being colonized by human glial cells have been successfully generated. However, generation of humanized chimeric mouse brains repopulated by human neurons to possess a high degree of chimerism have not been well studied. Here we created humanized neuronal chimeric mouse brains by neonatally engrafting the distinct and highly neurogenic human induced pluripotent stem cell (hiPSC)–derived rosette-type primitive neural progenitors. These neural progenitors predominantly differentiate to neurons, which disperse widely throughout the mouse brain with infiltration of the cerebral cortex and hippocampus at 6 and 13 months after transplantation. Building upon the hiPSC technology, we propose that this potentially unique humanized neuronal chimeric mouse model will provide profound opportunities to define the structure, function, and plasticity of neural networks containing human neurons derived from a broad variety of neurological disorders.

Authors

Chen Chen, Woo-Yang Kim, Peng Jiang

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Figure 1

Transplantation of hiPSC-pNPCs into the mouse brain.

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Transplantation of hiPSC-pNPCs into the mouse brain.
(A) A schematic dia...
(A) A schematic diagram showing the generation of humanized neuronal chimeric mouse brains. From left to right: neural rosettes derived from hiPSCs, nestin- and Pax6-expressing rosette-type hiPSC-pNPCs, stereotaxic injection of hiPSC-pNPCs into the neonatal mouse brain, and representative dot map showing the distribution of human nuclear antigen–positive (hN+) cells (in red) in 2 sagittal sections from 6-month- and 13-month-old mice. Notably, a small portion of the engrafted human cells is seen in the cerebellum. (B–E) Enlarged images from a sagittal section from a 13-month-old mouse showing the wide distribution of hN+ human cells in the hippocampus (HIP), cerebral cortex (CTX), striatum (STR), and the area near the injection site. Scale bars: 500 μm (B) and 100 μm (C–E). hiPSCs, human induced pluripotent stem cells; hiPSC-pNPCs, hiPSC-derived primitive neural progenitor cells.

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