INSIHGT: an accessible multi-scale, multi-modal 3D spatial biology platform

Chun Ngo Yau, Jacky Tin Shing Hung, Robert A. A. Campbell, Thomas Chun Yip Wong, Bei Huang, Ben Tin Yan Wong, Nick King Ngai Chow, Lichun Zhang, Eldric Pui Lam Tsoi, Yuqi Tan, Joshua Jing Xi Li, Yun Kwok Wing and Hei Ming Lai ()
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Chun Ngo Yau: The Chinese University of Hong Kong
Jacky Tin Shing Hung: The Chinese University of Hong Kong
Robert A. A. Campbell: University College London
Thomas Chun Yip Wong: The Chinese University of Hong Kong
Bei Huang: The Chinese University of Hong Kong
Ben Tin Yan Wong: The Chinese University of Hong Kong
Nick King Ngai Chow: The Chinese University of Hong Kong
Lichun Zhang: The Chinese University of Hong Kong
Eldric Pui Lam Tsoi: The Chinese University of Hong Kong
Yuqi Tan: Stanford University
Joshua Jing Xi Li: The University of Hong Kong, Queen Mary Hospital
Yun Kwok Wing: The Chinese University of Hong Kong
Hei Ming Lai: The Chinese University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Biological systems are complex, encompassing intertwined spatial, molecular and functional features. However, methodological constraints limit the completeness of information that can be extracted. Here, we report the development of INSIHGT, a non-destructive, accessible three-dimensional (3D) spatial biology method utilizing superchaotropes and host-guest chemistry to achieve homogeneous, deep penetration of macromolecular probes up to centimeter scales, providing reliable semi-quantitative signals throughout the tissue volume. Diverse antigens, mRNAs, neurotransmitters, and post-translational modifications are well-preserved and simultaneously visualized. INSIHGT also allows multi-round, highly multiplexed 3D molecular probing and is compatible with downstream traditional histology and nucleic acid sequencing. With INSIHGT, we map undescribed podocyte-to-parietal epithelial cell microfilaments in mouse glomeruli and neurofilament-intensive inclusion bodies in the human cerebellum, and identify NPY-proximal cell types defined by spatial morpho-proteomics in mouse hypothalamus. We anticipate that INSIHGT can form the foundations for 3D spatial multi-omics technology development and holistic systems biology studies.

Date: 2024
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DOI: 10.1038/s41467-024-55248-0

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