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
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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

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 2

Predominant neuronal differentiation of neonatally engrafted hiPSC-pNPCs in the mouse brain.

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Predominant neuronal differentiation of neonatally engrafted hiPSC-pNPCs...
(A and B) Representative images of βIII-tubulin– (βIIIT-), Dcx-, and NeuN-expressing neurons in the human nuclear antigen–positive (hN+) cells near the injection site 3 weeks after transplantation, and in the striatum (STR) at 6 and 13 months after transplantation. At 13 months, there are few hN+ cells that express GABA. Arrowheads in B indicate hN+/GABA+ neurons. The area in the white box is shown enlarged in the bottom-left corner. Scale bars: 50 μm (original) and 25 μm (enlarged). (C) The left panels show representative images of human-specific MAP2 (hMAP2)–expressing dendrites showing localization of foci of the excitatory synapse–specific PSD-95 protein in the STR. Scale bars: 50, 20, and 10 μm from top to bottom images, respectively. The right panels show representative images of c-Fos–expressing active neurons in the hN+ cells in the STR. Scale bar: 50 μm. (D) Representative images of Tbr1-expressing excitatory neurons in the hN+ cells in the superficial and deep layers of the cerebral cortex (CTX), and in the CA3 and dentate gyrus (DG) regions in the hippocampus at 13 months. The human neurons in the DG region are surrounded by synapsin-1 (Syn) staining. The area in the white box is enlarged in the 2 images below. Arrows indicate hN+/Tbr1– cells, and arrowheads indicate hN+/Tbr1+ cells. Scale bars: 50 μm (both original and enlarged images). Dcx, doublecortin; PSD-95, postsynaptic density-95.