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Pathology-oriented multiplexing enables integrative disease mapping

Malte Kuehl (), Yusuke Okabayashi (), Milagros N. Wong, Lukas Gernhold, Gabriele Gut, Nico Kaiser, Maria Schwerk, Stefanie K. Gräfe, Frank Y. Ma, Jovan Tanevski, Philipp S. L. Schäfer, Sam Mezher, Jacobo Sarabia del Castillo, Thiago Goldbeck-Strieder, Olga Zolotareva, Michael Hartung, Fernando M. Delgado Chaves, Lukas Klinkert, Ann-Christin Gnirck, Marc Spehr, David Fleck, Mehdi Joodaki, Victor Parra, Mina Shaigan, Martin Diebold, Marco Prinz, Jennifer Kranz, Johan M. Kux, Fabian Braun, Oliver Kretz, Hui Wu, Florian Grahammer, Sven Heins, Marina Zimmermann, Fabian Haas, Dominik Kylies, Nicola Wanner, Jan Czogalla, Bernhard Dumoulin, Nikolay Zolotarev, Maja Lindenmeyer, Pall Karlson, Jens R. Nyengaard, Marcial Sebode, Sören Weidemann, Thorsten Wiech, Hermann-Josef Groene, Nicola M. Tomas, Catherine Meyer-Schwesinger, Christoph Kuppe, Rafael Kramann, Alexandre Karras, Patrick Bruneval, Pierre-Louis Tharaux, Diego Pastene, Benito Yard, Jennifer A. Schaub, Phillip J. McCown, Laura Pyle, Ye Ji Choi, Takashi Yokoo, Jan Baumbach, Pablo J. Sáez, Ivan Costa, Jan-Eric Turner, Jeffrey B. Hodgin, Julio Saez-Rodriguez, Tobias B. Huber, Petter Bjornstad, Matthias Kretzler, Olivia Lenoir, David J. Nikolic-Paterson, Lucas Pelkmans, Stefan Bonn and Victor G. Puelles ()
Additional contact information
Malte Kuehl: Aarhus University
Yusuke Okabayashi: University Medical Center Hamburg-Eppendorf
Milagros N. Wong: Aarhus University
Lukas Gernhold: University Medical Center Hamburg-Eppendorf
Gabriele Gut: University of Zurich
Nico Kaiser: University Medical Center Hamburg-Eppendorf
Maria Schwerk: University Medical Center Hamburg-Eppendorf
Stefanie K. Gräfe: University Medical Center Hamburg-Eppendorf
Frank Y. Ma: Monash University
Jovan Tanevski: Heidelberg University and Heidelberg University Hospital
Philipp S. L. Schäfer: Heidelberg University and Heidelberg University Hospital
Sam Mezher: University Medical Center Hamburg-Eppendorf
Jacobo Sarabia del Castillo: University of Zurich
Thiago Goldbeck-Strieder: University Medical Center Hamburg-Eppendorf
Olga Zolotareva: University of Hamburg
Michael Hartung: University of Hamburg
Fernando M. Delgado Chaves: University of Hamburg
Lukas Klinkert: University Medical Center Hamburg-Eppendorf
Ann-Christin Gnirck: University Medical Center Hamburg-Eppendorf
Marc Spehr: RWTH Aachen University
David Fleck: RWTH Aachen University
Mehdi Joodaki: RWTH Aachen University
Victor Parra: RWTH Aachen University
Mina Shaigan: RWTH Aachen University
Martin Diebold: University of Freiburg
Marco Prinz: University of Freiburg
Jennifer Kranz: University Hospital RWTH Aachen
Johan M. Kux: University Medical Center Hamburg-Eppendorf
Fabian Braun: University Medical Center Hamburg-Eppendorf
Oliver Kretz: University Medical Center Hamburg-Eppendorf
Hui Wu: University Medical Center Hamburg-Eppendorf
Florian Grahammer: University Medical Center Hamburg-Eppendorf
Sven Heins: University Medical Center Hamburg-Eppendorf
Marina Zimmermann: University Medical Center Hamburg-Eppendorf
Fabian Haas: University Medical Center Hamburg-Eppendorf
Dominik Kylies: University Medical Center Hamburg-Eppendorf
Nicola Wanner: University Medical Center Hamburg-Eppendorf
Jan Czogalla: University Medical Center Hamburg-Eppendorf
Bernhard Dumoulin: University Medical Center Hamburg-Eppendorf
Nikolay Zolotarev: University Medical Center Hamburg-Eppendorf
Maja Lindenmeyer: University Medical Center Hamburg-Eppendorf
Pall Karlson: Aarhus University
Jens R. Nyengaard: Aarhus University
Marcial Sebode: University Medical Center Hamburg-Eppendorf
Sören Weidemann: University Medical Centre Hamburg-Eppendorf
Thorsten Wiech: University Medical Center Hamburg-Eppendorf
Hermann-Josef Groene: University Medical Center Hamburg-Eppendorf
Nicola M. Tomas: University Medical Center Hamburg-Eppendorf
Catherine Meyer-Schwesinger: University Medical Center Hamburg-Eppendorf
Christoph Kuppe: Medical Faculty
Rafael Kramann: Medical Faculty
Alexandre Karras: Université Paris Cité
Patrick Bruneval: Paris Cardiovascular Research Center (PARCC)
Pierre-Louis Tharaux: Paris Cardiovascular Research Center (PARCC)
Diego Pastene: University of Heidelberg
Benito Yard: University of Heidelberg
Jennifer A. Schaub: University of Michigan
Phillip J. McCown: University of Michigan
Laura Pyle: University of Washington
Ye Ji Choi: University of Washington
Takashi Yokoo: The Jikei University School of Medicine
Jan Baumbach: University of Hamburg
Pablo J. Sáez: University Medical Center Hamburg-Eppendorf
Ivan Costa: RWTH Aachen University
Jan-Eric Turner: University Medical Center Hamburg-Eppendorf
Jeffrey B. Hodgin: University of Michigan
Julio Saez-Rodriguez: Heidelberg University and Heidelberg University Hospital
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Petter Bjornstad: University of Washington
Matthias Kretzler: University of Michigan
Olivia Lenoir: Paris Cardiovascular Research Center (PARCC)
David J. Nikolic-Paterson: Monash University
Lucas Pelkmans: University of Zurich
Stefan Bonn: University Medical Center Hamburg-Eppendorf
Victor G. Puelles: Aarhus University

Nature, 2025, vol. 644, issue 8076, 516-526

Abstract: Abstract The expression and location of proteins in tissues represent key determinants of health and disease. Although recent advances in multiplexed imaging have expanded the number of spatially accessible proteins1–3, the integration of biological layers (that is, cell structure, subcellular domains and signalling activity) remains challenging. This is due to limitations in the compositions of antibody panels and image resolution, which together restrict the scope of image analysis. Here we present pathology-oriented multiplexing (PathoPlex), a scalable, quality-controlled and interpretable framework. It combines highly multiplexed imaging at subcellular resolution with a software package to extract and interpret protein co-expression patterns (clusters) across biological layers. PathoPlex was optimized to map more than 140 commercial antibodies at 80 nm per pixel across 95 iterative imaging cycles and provides pragmatic solutions to enable the simultaneous processing of at least 40 archival biopsy specimens. In a proof-of-concept experiment, we identified epithelial JUN activity as a key switch in immune-mediated kidney disease, thereby demonstrating that clusters can capture relevant pathological features. PathoPlex was then used to analyse human diabetic kidney disease. The framework linked patient-level clusters to organ disfunction and identified disease traits with therapeutic potential (that is, calcium-mediated tubular stress). Finally, PathoPlex was used to reveal renal stress-related clusters in individuals with type 2 diabetes without histological kidney disease. Moreover, tissue-based readouts were generated to assess responses to inhibitors of the glucose cotransporter SGLT2. In summary, PathoPlex paves the way towards democratizing multiplexed imaging and establishing integrative image analysis tools in complex tissues to support the development of next-generation pathology atlases.

Date: 2025
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DOI: 10.1038/s41586-025-09225-2

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