Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

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.

A Bioinformatics Model of Human Diseases on the Basis of Differentially Expressed Genes (of Domestic Versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes

“…Human gene PDGFRA encodes platelet-derived growth factor receptor α, both a deficit and excess of which worsen reproductive potential through skeletal defects in newborns [ 75 ] and predisposition to infertility after infections [ 76 ] ( Table 4 ).…”

A review of physiological and cellular mechanisms underlying fibrotic postoperative adhesion

“…Mechanically, MSLN + MCs is the important subpopulation of MCs involved in the development of adhesion. Foster et al 41 recently found that JUN expression was strongly induced and correlated with prominent MSLN expression, and inhibition of JUN significantly minimizes adhesion formation.…”

Post-Surgical Peritoneal Scarring and Key Molecular Mechanisms

“…Of importance, Foster et al analysed adhesions from patients and mouse models to elucidate the heterogeneity and source of fibrogenic cells. Fibroblasts within adhesions were found to express platelet derived growth factor receptor alpha (PDGFRA), a transmembrane receptor tyrosine kinase, as well as fibroblast markers, such as αSMA, vimentin, and collagen 1 (COL1) [ 92 ]. In murine ischaemic tissue-induced adhesions, fibroblasts expressed JUN (proto-oncogene, named after viral homolog v-jun in avian sarcoma virus 17), which is a transcriptional master regulator of fibrogenesis, and a portion of these cells were also positive for the mesothelial marker mesothelin (MSLN).…”

“…Analysis of these clusters in relation to their timepoints revealed that early JUN activation promoted a profibrotic state as reflected in the expression profiles. Moreover, inhibition of the highly expressed Jun/Jak/Stat pathway was found to reduce adhesion formation and was proposed as a novel preventative strategy [ 92 ].…”

“…Mesothelial cells have been proposed as another important source of fibrogenic cells that mediate adhesion formation through a process of MMT. Using human adhesion samples, Foster and colleagues demonstrated that a small portion of JUN+ fibroblasts also expressed the mesothelial marker MSLN and the EMT pathway was one of the most significantly upregulated molecular profiles in cultured adhesion fibroblasts [ 92 ]. Sandoval and colleagues also analysed human adhesions and showed co-localisation of the epithelial marker, cytokeratin and the mesenchymal marker, αSMA, in spindle-like cells in the subserosa strongly implicating that mesothelial cells had transitioned to become myofibroblasts [ 97 ], a feature commonly found in biopsy samples from peritoneal dialysis patients [ 54 ].…”