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Sci Transl Med. 2018 Nov 28;10(469). pii: eaan6735. doi: 10.1126/scitranslmed.aan6735.

Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
AI based Healthcare and Medical Data Analysis Standardization Unit, Medical Sciences Innovation Hub Program, RIKEN, Tokyo 103-0027, Japan.
4
Comprehensive Pneumology Center, Institute of Lung Biology and Disease,Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
5
Department of General Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Cell Sciences Imaging Facility, Beckman Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. yuval.rinkevich@helmholtz-muenchen.de irv@stanford.edu.
9
Ludwig Center for Cancer Stem Cell Biology and Medicine at Stanford University, Stanford, CA 94305, USA.
10
Comprehensive Pneumology Center, Institute of Lung Biology and Disease,Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany. yuval.rinkevich@helmholtz-muenchen.de irv@stanford.edu.

Abstract

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and are a major cause of postsurgical and infectious morbidity. The primary molecular chain of events leading to the initiation of adhesions has been elusive, chiefly due to the lack of an identifiable cell of origin. Using clonal analysis and lineage tracing, we have identified injured surface mesothelium expressing podoplanin (PDPN) and mesothelin (MSLN) as a primary instigator of peritoneal adhesions after surgery in mice. We demonstrate that an anti-MSLN antibody diminished adhesion formation in a mouse model where adhesions were induced by surgical ligation to form ischemic buttons and subsequent surgical abrasion of the peritoneum. RNA sequencing and bioinformatics analyses of mouse mesothelial cells from injured mesothelium revealed aspects of the pathological mechanism of adhesion development and yielded several potential regulators of this process. Specifically, we show that PDPN+MSLN+ mesothelium responded to hypoxia by early up-regulation of hypoxia-inducible factor 1 alpha (HIF1α) that preceded adhesion development. Inhibition of HIF1α with small molecules ameliorated the injury program in damaged mesothelium and was sufficient to diminish adhesion severity in a mouse model. Analyses of human adhesion tissue suggested that similar surface markers and signaling pathways may contribute to surgical adhesions in human patients.

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