Optics-free spatial genomics for mapping mammalian brain aging by IRISeq
5 affiliations
- 1Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA
- 2The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA
- 3The Tri-Institutional M.D-Ph.D Program, New York, NY, USA
- 4Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA. [email protected]
- 5Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA. [email protected]
Abstract
Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.
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BibTeX
@article{abdulraouf2026opticsfree,
title = {{Optics-free spatial genomics for mapping mammalian brain aging by IRISeq}},
author = {Abdulraouf Abdulraouf and Weirong Jiang and Zehao Zhang and Zihan Xu and Ziyu Lu and Tiffany R. Merlinsky and Andrew Liao and Ahmet Doymaz and Samuel Isakov and Tanvir Raihan and Wei You Zhou and Junyue Cao},
journal = {Nature Neuroscience},
year = {2026},
month = may,
doi = {10.1038/s41593-026-02293-1},
url = {https://doi.org/10.1038/s41593-026-02293-1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Optics-free spatial genomics for mapping mammalian brain aging by IRISeq
AU - Abdulraouf Abdulraouf
AU - Weirong Jiang
AU - Zehao Zhang
AU - Zihan Xu
AU - Ziyu Lu
AU - Tiffany R. Merlinsky
AU - Andrew Liao
AU - Ahmet Doymaz
AU - Samuel Isakov
AU - Tanvir Raihan
AU - Wei You Zhou
AU - Junyue Cao
PY - 2026
DA - 2026/05/12
JO - Nature Neuroscience
DO - 10.1038/s41593-026-02293-1
UR - https://doi.org/10.1038/s41593-026-02293-1
AB - Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.
SN - 1097-6256
SN - 1546-1726
ER -