PMID- 34608315 OWN - NLM STAT- MEDLINE VI - 18 IP - 10 TI - SEAM is a spatial single nuclear metabolomics method for dissecting tissue microenvironment. PG - 1223-1232 CI - © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Nat Methods JT - Nature methods JID - 101215604 IS - 1548-7105 (Electronic) LID - 10.1038/s41592-021-01276-3 [doi] FAU - Yuan, Zhiyuan AU - Yuan Z AUID- ORCID: http://orcid.org/0000-0002-9367-4236 AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Institute of TCM-X, Department of Automation, Tsinghua University, Beijing, China. FAU - Zhou, Qiming AU - Zhou Q AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, School of Life Sciences, Tsinghua University, Beijing, China. FAU - Cai, Lesi AU - Cai L AD - Department of Chemistry, Tsinghua University, Beijing, China. FAU - Pan, Lin AU - Pan L AD - Institute of Clinical Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China. FAU - Sun, Weiliang AU - Sun W AD - Institute of Clinical Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China. FAU - Qumu, Shiwei AU - Qumu S AD - Department of Pulmonary and Critical Care Medicine, China-Japan Friend Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China. FAU - Yu, Si AU - Yu S AD - Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Feng, Jiaxin AU - Feng J AD - Department of Chemistry, Tsinghua University, Beijing, China. FAU - Zhao, Hansen AU - Zhao H AUID- ORCID: http://orcid.org/0000-0003-2978-5756 AD - Department of Chemistry, Tsinghua University, Beijing, China. FAU - Zheng, Yongchang AU - Zheng Y AUID- ORCID: http://orcid.org/0000-0002-5916-2392 AD - Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Shi, Minglei AU - Shi M AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. FAU - Li, Shao AU - Li S AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Institute of TCM-X, Department of Automation, Tsinghua University, Beijing, China. FAU - Chen, Yang AU - Chen Y AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Institute of TCM-X, Department of Automation, Tsinghua University, Beijing, China. yc@ibms.pumc.edu.cn. AD - The State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China. yc@ibms.pumc.edu.cn. FAU - Zhang, Xinrong AU - Zhang X AUID- ORCID: http://orcid.org/0000-0002-3174-303X AD - Department of Chemistry, Tsinghua University, Beijing, China. xrzhang@mail.tsinghua.edu.cn. FAU - Zhang, Michael Q AU - Zhang MQ AUID- ORCID: http://orcid.org/0000-0002-7022-6115 AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Institute of TCM-X, Department of Automation, Tsinghua University, Beijing, China. michael.zhang@utdallas.edu. AD - MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. michael.zhang@utdallas.edu. AD - Department of Biological Sciences, Center for Systems Biology, The University of Texas, Richardson, TX, USA. michael.zhang@utdallas.edu. IS - 1548-7091 (Linking) SB - IM MH - Algorithms MH - Animals MH - *Cellular Microenvironment MH - Computational Biology/*methods MH - Hepatocytes/physiology MH - Humans MH - Liver/*cytology/physiology MH - Liver Cirrhosis/*metabolism MH - Metabolomics/methods MH - Mice MH - Reproducibility of Results MH - Single Molecule Imaging MH - Transcriptome DCOM- 20211115 LR - 20230207 DP - 202110 DEP - 20211004 AB - Spatial metabolomics can reveal intercellular heterogeneity and tissue organization. Here we report on the spatial single nuclear metabolomics (SEAM) method, a flexible platform combining high-spatial-resolution imaging mass spectrometry and a set of computational algorithms that can display multiscale and multicolor tissue tomography together with identification and clustering of single nuclei by their in situ metabolic fingerprints. We first applied SEAM to a range of wild-type mouse tissues, then delineated a consistent pattern of metabolic zonation in mouse liver. We further studied the spatial metabolic profile in the human fibrotic liver. We discovered subpopulations of hepatocytes with special metabolic features associated with their proximity to the fibrotic niche, and validated this finding by spatial transcriptomics with Geo-seq. These demonstrations highlighted SEAM's ability to explore the spatial metabolic profile and tissue histology at the single-cell level, leading to a deeper understanding of tissue metabolic organization.