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.
Highlights
Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility
JUN is a member of the Activator Protein-1 (AP-1) transcription factor complex, which has conserved function in mice and humans, and was recently found to promote fibrotic disease in the lung, skin, bone marrow, kidney, liver, pancreas, and heart[6]
We found that JUN expression is an early promotor of abdominal adhesions, which upregulates signaling of several pathways known to result in fibrosis including JAK-STAT, epithelial-mesenchymal transition (EMT), as well as PDGFRA expression
Summary
Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. We investigate the origin of adhesion-forming cells, and show using in vivo models that adhesions derive primarily from the visceral peritoneum This is in line with our clinical observation that adhesions are most severe following open abdominal surgical procedures that involve manipulation of the bowel (Supplementary Fig. 1a–c). Using bulk and single-cell RNA-seq, we explore patterns of gene expression and heterogeneity among abdominal adhesion fibroblasts derived from mouse and human tissue specimens. These data suggest that JUN is a transcriptional master regulator of fibroblasts in the context of abdominal adhesions. Our findings suggest that an anti-JUN therapy might be effective to prevent adhesions clinically
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