Abstract
Peritoneal fibrosis is a common complication of abdominal and pelvic surgery, and can also be triggered by peritoneal dialysis, resulting in treatment failure. In these settings, fibrosis is driven by activated myofibroblasts that are considered to be partly derived by mesothelial‐to‐mesenchymal transition (MMT). We hypothesized that, if the molecular signature of MMT could be better defined, these insights could be exploited to block this pathological cellular transition. Rat peritoneal mesothelial cells were purified by the use of an antibody against HBME1, a protein present on mesothelial cell microvilli, and streptavidin nanobead technology. After exposure of sorted cells to a well‐known mediator of MMT, transforming growth factor (TGF)‐β1, RNA sequencing was undertaken to define the transcriptomes of mesothelial cells before and during early‐phase MMT. MMT was associated with dysregulation of transcripts encoding molecules involved in insulin‐like growth factor (IGF) and bone morphogenetic protein (BMP) signalling. The application of either recombinant BMP4 or IGF‐binding protein 4 (IGFBP4) ameliorated TGF‐β1‐induced MMT in culture, as judged from the retention of epithelial morphological and molecular phenotypes, and reduced migration. Furthermore, peritoneal tissue from peritoneal dialysis patients showed less prominent immunostaining than control tissue for IGFBP4 and BMP4 on the peritoneal surface. In a mouse model of TGF‐β1‐induced peritoneal thickening, BMP4 immunostaining on the peritoneal surface was attenuated as compared with healthy controls. Finally, genetic lineage tracing of mesothelial cells was used in mice with peritoneal injury. In this model, administration of BMP4 ameliorated the injury‐induced shape change and migration of mesothelial cells. Our findings demonstrate a distinctive MMT signature, and highlight the therapeutic potential for BMP4, and possibly IGFBP4, to reduce MMT. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Epithelia form sheets and tubules conferring physical integrity and performing physiological functions
fluorescence-activated cell sorting (FACS) and magnetic bead sorting each resulted in significant enrichment of cells expressing HBME1 (Figure 1B,C) or Wt1 (Figure 1B,D), an Mesothelial cells (MCs) transcription factor [4,5]
In a mouse model of peritoneal fibrosis induced by intraperitoneal transforming growth factor (TGF)-β1-expressing adenovirus, there was attenuation of BMP4 immunostaining of the surface of the peritoneum (Figure 5A)
Summary
Epithelia form sheets and tubules conferring physical integrity and performing physiological functions. Epithelial-to-mesenchymal transition (EMT) occurs in normal development during gastrulation and neural crest migration. EMT is characterized by disrupted cell–cell adhesion and apical–basolateral polarity, cytoskeletal reorganization, detachment from basement membranes, and the generation of motile mesenchymal cells. Mesothelial cells (MCs) are epithelial-like cells lining the coelomic cavities and the organs that they contain. MCs have junctional complexes and apical–basolateral polarity, and adhere to a basement membrane. MCs in vivo express cytokeratins, which is characteristic of epithelia, and vimentin, which is more typical of mesenchyme [3]. Some MCs undergo mesothelial-to-mesenchymal transition (MMT) to form vascular smooth muscle [4,5]. MCs are not typical epithelial cells, so the biological characteristics of MMT and EMT may not be identical
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