Human Neural Progenitor Cells Incorporate into Functional Network in Mouse Hippocampus

Jiani Hong; Liuqing Yang

doi:10.6911/WSRJ.202606_12(6).0002

Authors

Jiani Hong
Liuqing Yang

DOI:

https://doi.org/10.6911/WSRJ.202606_12(6).0002

Keywords:

iNPCs; hippocampus xenotransplantation; functional integration.

Abstract

Human neural progenitor cell (NPC) transplantation into mouse brain has been widely used as an in vivo human-relevant model system. The integration of differentiated human cells or tissue with local circuit has also been intensively investigated. However, as part of the central nervous system which governs the behaviors of living organisms, evidence on whether xenografted neurons are responsive to mouse behavior in intended ways is still poor. In this work, we transplanted iPSC-derived NPCs (iNPCs) into the hilus region of mouse hippocampus and monitored their survival, migration, differentiation and integration in different host mouse lines for different timespan. We found that iNPCs survived for up to two months in C57BL6 mice and for more than six months in Rag2 KO immunodeficient mice. To assess functional integration, we performed contextual fear conditioning with Rag2 KO xenograft mice and examined endogenous Fos protein expression. Dentate gyrus neurons are largely silent and sparsely activated during contextual information learning. We found that fear conditioning training induces Fos gene expression in iNPC-differentiated neurons 6 months after transplantation. The result suggests that behavior-responsive functional integration of human xenografted neurons in mouse hippocampus can be formed after long-time integration.

Downloads

Download data is not yet available.

References

[1] Linaro, D., Vermaercke, B., Iwata, R., et al. (2019). Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits. Neuron, 104(5), 972–986.e6. https://doi.org/10.1016/j.neuron.2019.09.032.

[2] Balusu, S., Horré, K., Thrupp, N., et al. (2023). MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. Science, 381(6663), 1176–1182. https://doi.org/10.1126/science.add4945

[3] Weber, R. Z., Achón Buil, B., Rentsch, N. H., et al. (2025). Neural xenografts contribute to long-term recovery in stroke via molecular graft-host crosstalk. Nature Communications, 16(1), 8224. https://doi.org/10.1038/s41467-025-63369-7

[4] Mansour, A. A., Gonçalves, J. T., Bloyd, C. W., et al. (2018). An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology, 36(5), 432–441. https://doi.org/10.1038/nbt.4132

[5] Wang, M., Zhang, L., Novak, S. W., et al. (2025). Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain. Nature Biotechnology, 43(1), 52–62. https://doi.org/10.1038/s41587-024-02247-0

[6] Dong, X., Xu, S. B., Chen, X., et al. (2021). Human cerebral organoids establish subcortical projections in the mouse brain after transplantation. Molecular Psychiatry, 26(7), 2964–2976. https://doi.org/10.1038/s41380-020-00991-7

[7] Fattorelli, N., Martinez-Muriana, A., Wolfs, L., et al. (2021). Stem-cell-derived human microglia transplanted into mouse brain to study human disease. Nature Protocols, 16(2), 1013–1033. https://doi.org/10.1038/s41596-020-00464-0

[8] Pașca, S. P. (2024). Constructing human neural circuits in living systems by transplantation. Cell, 187(1), 8–13. https://doi.org/10.1016/j.cell.2023.12.012

[9] Han, X., Chen, M., Wang, F., et al. (2013). Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell, 12(3), 342–353. https://doi.org/10.1016/j.stem.2013.01.015

[10] Josselyn, S. A., & Tonegawa, S. (2020). Memory engrams: Recalling the past and imagining the future. Science, 367(6473), eaaw4325. https://doi.org/10.1126/science.aaw4325

[11] Chen, S., He, L., Huang, A. J. Y., et al. (2020). A hypothalamic novelty signal modulates hippocampal memory. Nature, 586(7828), 270–274. https://doi.org/10.1038/s41586-020-2771-1

[12] Ramirez, S., Liu, X., Lin, P. A., et al. (2013). Creating a false memory in the hippocampus. Science, 341(6144), 387–391. https://doi.org/10.1126/science.1239073

[13] Liu, X., Ramirez, S., Pang, P. T., et al. (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 484(7394), 381–385. https://doi.org/10.1038/nature11028

[14] Denny, C. A., Kheirbek, M. A., Alba, E. L., et al. (2014). Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron, 83(1), 189–201. https://doi.org/10.1016/j.neuron.2014.05.013

[15] Han, J. H., Kushner, S. A., Yiu, A. P., et al. (2009). Selective erasure of a fear memory. Science, 323(5920), 1492–1496. https://doi.org/10.1126/science.1164139

[16] Roy, D. S., Park, Y. G., Kim, M. E., et al. (2022). Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions. Nature Communications, 13(1), 1799. https://doi.org/10.1038/s41467-022-29445-0

[17] Sagar, S. M., Sharp, F. R., & Curran, T. (1988). Expression of c-fos protein in brain: Metabolic mapping at the cellular level. Science, 240(4857), 1328–1331. https://doi.org/10.1126/science.3287646

[18] Kim, Y., Venkataraju, K. U., Pradhan, K., et al. (2015). Mapping social behavior-induced brain activation at cellular resolution in the mouse. Cell Reports, 10(2), 292–305. https://doi.org/10.1016/j.celrep.2014.12.022

[19] Yu, X., Pang, P., Liu, T., et al. (2025). Brain-wide mapping of acute hypoxia-induced neuronal activation in mice: A c-Fos immunofluorescence study. IBRO Neuroscience Reports, 19, 519–531. https://doi.org/10.1016/j.ibror.2025.05.004

[20] Hu, Y., Du, W., Qi, J., et al. (2024). Comparative brain-wide mapping of ketamine- and isoflurane-activated nuclei and functional networks in the mouse brain. eLife, 12, RP88420. https://doi.org/10.7554/eLife.88420

[21] Yang, H., Shan, W., Zhu, F., et al. (2019). C-Fos mapping and EEG characteristics of multiple mice brain regions in pentylenetetrazol-induced seizure mice model. Neurological Research, 41(8), 749–761. https://doi.org/10.1080/01616412.2019.1617802

[22] Fredes, F., Silva, M. A., Koppensteiner, P., et al. (2021). Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation. Current Biology, 31(1), 25–38.e5. https://doi.org/10.1016/j.cub.2020.10.070

[23] Choi, J. H., Sim, S. E., Kim, J. I., et al. (2018). Interregional synaptic maps among engram cells underlie memory formation. Science, 360(6387), 430–435. https://doi.org/10.1126/science.aas9325

[24] Leutgeb, J. K., Leutgeb, S., Moser, M. B., et al. (2007). Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science, 315(5814), 961–966. https://doi.org/10.1126/science.1135801