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

Author:

Fischer Adrian,Koopmans Tim,Ramesh Pushkar,Christ SimonORCID,Strunz Maximilian,Wannemacher Juliane,Aichler Michaela,Feuchtinger Annette,Walch Axel,Ansari MeshalORCID,Theis Fabian J.ORCID,Schorpp Kenji,Hadian KamyarORCID,Neumann Philipp-Alexander,Schiller Herbert B.ORCID,Rinkevich Yuval

Abstract

AbstractSurgical 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.

Funder

Deutsche Forschungsgemeinschaft

Else Kröner-Fresenius-Stiftung

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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