Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Deshka S. Foster, Clement D. Marshall, Gunsagar S. Gulati, Malini S. Chinta, Alan Nguyen, Ankit Salhotra, R. Ellen Jones, Austin Burcham, Tristan Lerbs, Lu Cui, Megan E. King, Ashley L. Titan, R. Chase Ransom, Anoop Manjunath, Michael S. Hu, Charles P. Blackshear, Shamik Mascharak, Alessandra L. Moore, Jeffrey A. Norton, Cindy J. Kin, Andrew A. Shelton, Michael Januszyk, Geoffrey C. Gurtner, Gerlinde Wernig () and Michael T. Longaker ()
Additional contact information
Deshka S. Foster: Stanford University School of Medicine
Clement D. Marshall: Stanford University School of Medicine
Gunsagar S. Gulati: Stanford University School of Medicine
Malini S. Chinta: Stanford University School of Medicine
Alan Nguyen: Stanford University School of Medicine
Ankit Salhotra: Stanford University School of Medicine
R. Ellen Jones: Stanford University School of Medicine
Austin Burcham: Stanford University School of Medicine
Tristan Lerbs: Stanford University School of Medicine
Lu Cui: Stanford University School of Medicine
Megan E. King: Stanford University School of Medicine
Ashley L. Titan: Stanford University School of Medicine
R. Chase Ransom: Stanford University School of Medicine
Anoop Manjunath: Stanford University School of Medicine
Michael S. Hu: Stanford University School of Medicine
Charles P. Blackshear: Stanford University School of Medicine
Shamik Mascharak: Stanford University School of Medicine
Alessandra L. Moore: Stanford University School of Medicine
Jeffrey A. Norton: Stanford University School of Medicine
Cindy J. Kin: Stanford University School of Medicine
Andrew A. Shelton: Stanford University School of Medicine
Michael Januszyk: Stanford University School of Medicine
Geoffrey C. Gurtner: Stanford University School of Medicine
Gerlinde Wernig: Stanford University School of Medicine
Michael T. Longaker: Stanford University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.

Date: 2020
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DOI: 10.1038/s41467-020-17883-1

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