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Molecular landscapes of human hippocampal immature neurons across lifespan

Author

Listed:
  • Yi Zhou

    (University of Pennsylvania)

  • Yijing Su

    (University of Pennsylvania)

  • Shiying Li

    (University of Pennsylvania
    Nantong University)

  • Benjamin C. Kennedy

    (Division of Neurosurgery, Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • 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
    The Epilepsy NeuroGenetics Initiative (ENGIN), Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Sudha K. Kessler

    (Division of Neurology, Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Timothy Lucas

    (University of Pennsylvania)

  • Ryan D. Salinas

    (University of Pennsylvania)

  • Xiaosong Gu

    (Nantong University)

  • H. Isaac Chen

    (University of Pennsylvania
    University of Pennsylvania)

  • Hao Wu

    (University of Pennsylvania
    University of Pennsylvania
    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
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Hongjun Song

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

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.

Suggested Citation

  • 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 Luca, 2022. "Molecular landscapes of human hippocampal immature neurons across lifespan," Nature, Nature, vol. 607(7919), pages 527-533, July.
  • Handle: RePEc:nat:nature:v:607:y:2022:i:7919:d:10.1038_s41586-022-04912-w
    DOI: 10.1038/s41586-022-04912-w
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    Citations

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    Cited by:

    1. Ting Zhao & Yan Hong & Bowen Yan & Suming Huang & Guo-li Ming & Hongjun Song, 2024. "Epigenetic maintenance of adult neural stem cell quiescence in the mouse hippocampus via Setd1a," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. P. Bielefeld & A. Martirosyan & S. Martín-Suárez & A. Apresyan & G. F. Meerhoff & F. Pestana & S. Poovathingal & N. Reijner & W. Koning & R. A. Clement & I. Veen & E. M. Toledo & O. Polzer & I. Durá &, 2024. "Traumatic brain injury promotes neurogenesis at the cost of astrogliogenesis in the adult hippocampus of male mice," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Yuhao Min & Xue Wang & Özkan İş & Tulsi A. Patel & Junli Gao & Joseph S. Reddy & Zachary S. Quicksall & Thuy Nguyen & Shu Lin & Frederick Q. Tutor-New & Jessica L. Chalk & Adriana O. Mitchell & Julia , 2023. "Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. M. Agustina Frechou & Sunaina S. Martin & Kelsey D. McDermott & Evan A. Huaman & Şölen Gökhan & Wolfgang A. Tomé & Ruben Coen-Cagli & J. Tiago Gonçalves, 2024. "Adult neurogenesis improves spatial information encoding in the mouse hippocampus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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