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Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers.
Sci. Transl. Med. 10:eaan6735 (2018)
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 (HIF1 alpha) that preceded adhesion development. Inhibition of HIF1. 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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Postoperative Adhesion; Peritoneal Adhesions; Neurokinin-1 Receptor; Cancer; Regeneration; Pathogenesis; Replication; Fibroblasts; Prevention; Lineage
ISSN (print) / ISBN
1946-6234
e-ISSN
1946-6242
Zeitschrift
Science Translational Medicine
Quellenangaben
Band: 10,
Heft: 469,
Artikelnummer: eaan6735
Verlag
American Association for the Advancement of Science (AAAS)
Verlagsort
1200 New York Ave, Nw, Washington, Dc 20005 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed