Molecular landscapes of human hippocampal immature neurons across lifespan

Yi Zhou, Yijing Su, Shiying Li, Benjamin C. Kennedy, Daniel Y. Zhang, Allison M. Bond, Yusha Sun, Fadi Jacob, Lu Lu, Peng Hu, Angela N. Viaene, Ingo Helbig, Sudha K. Kessler, Timothy Lucas, Ryan D. Salinas, Xiaosong Gu, H. Isaac Chen, Hao Wu, Joel E. Kleinman, Thomas M. Hyde, David W. Nauen, Daniel R. Weinberger, Guo-li Ming () and Hongjun Song ()
Additional contact information
Yi Zhou: University of Pennsylvania
Yijing Su: University of Pennsylvania
Shiying Li: University of Pennsylvania
Benjamin C. Kennedy: Division of Neurosurgery, Children’s Hospital of Philadelphia
Daniel Y. Zhang: University of Pennsylvania
Allison M. Bond: University of Pennsylvania
Yusha Sun: University of Pennsylvania
Fadi Jacob: University of Pennsylvania
Lu Lu: University of Pennsylvania
Peng Hu: University of Pennsylvania
Angela N. Viaene: Children’s Hospital of Philadelphia
Ingo Helbig: Division of Neurology, Children’s Hospital of Philadelphia
Sudha K. Kessler: Division of Neurology, Children’s Hospital of Philadelphia
Timothy Lucas: University of Pennsylvania
Ryan D. Salinas: University of Pennsylvania
Xiaosong Gu: Nantong University
H. Isaac Chen: University of Pennsylvania
Hao Wu: University of Pennsylvania
Joel E. Kleinman: Lieber Institute for Brain Development, The Solomon H. Snyder Department of Neuroscience, Department of Neurology, and Department of Psychiatry, School of Medicine, Johns Hopkins University
Thomas M. Hyde: Lieber Institute for Brain Development, The Solomon H. Snyder Department of Neuroscience, Department of Neurology, and Department of Psychiatry, School of Medicine, Johns Hopkins University
David W. Nauen: Johns Hopkins University School of Medicine
Daniel R. Weinberger: Lieber Institute for Brain Development, The Solomon H. Snyder Department of Neuroscience, Department of Neurology, and Department of Psychiatry, School of Medicine, Johns Hopkins University
Guo-li Ming: University of Pennsylvania
Hongjun Song: University of Pennsylvania

Nature, 2022, vol. 607, issue 7919, 527-533

Abstract: Abstract Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3–5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6–8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.

Date: 2022
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DOI: 10.1038/s41586-022-04912-w

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