Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces

Adrian Fischer, Tim Koopmans, Pushkar Ramesh, Simon Christ, Maximilian Strunz, Juliane Wannemacher, Michaela Aichler, Annette Feuchtinger, Axel Walch, Meshal Ansari, Fabian J. Theis, Kenji Schorpp, Kamyar Hadian, Philipp-Alexander Neumann, Herbert B. Schiller and Yuval Rinkevich ()
Additional contact information
Adrian Fischer: Member of the German Center for Lung Research (DZL)
Tim Koopmans: Member of the German Center for Lung Research (DZL)
Pushkar Ramesh: Member of the German Center for Lung Research (DZL)
Simon Christ: Member of the German Center for Lung Research (DZL)
Maximilian Strunz: Member of the German Center for Lung Research (DZL)
Juliane Wannemacher: Member of the German Center for Lung Research (DZL)
Michaela Aichler: Helmholtz Zentrum München
Annette Feuchtinger: Helmholtz Zentrum München
Axel Walch: Helmholtz Zentrum München
Meshal Ansari: Institute of Computational Biology
Fabian J. Theis: Institute of Computational Biology
Kenji Schorpp: Institute for Molecular Toxicology and Pharmacology
Kamyar Hadian: Institute for Molecular Toxicology and Pharmacology
Philipp-Alexander Neumann: Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery
Herbert B. Schiller: Member of the German Center for Lung Research (DZL)
Yuval Rinkevich: Member of the German Center for Lung Research (DZL)

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions.

Date: 2020
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DOI: 10.1038/s41467-020-16893-3

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