Myofibroblastic conversion of mesothelial cells.
BACKGROUND
The continuous chemical, physical, and inflammatory insults of prolonged continuous ambulatory peritoneal dialysis (CAPD) incite mesothelial cell responses, which may result in peritoneal fibrosis. The transforming growth factor-beta (TGF-beta), especially the isoform TGF-beta 1, has long been known to play crucial role in the fibrogenic process. Although several studies have implicated TGF-beta in peritoneal fibrosis, the underlying mechanism has not been completely elucidated.


METHODS
To test the effects of exogenous TGF-beta 1 on mesothelial cells, we assessed cytoarchitectural changes of human peritoneal mesothelial cells (HPMC) in in vitro culture by light, immunofluorescent, electron and immunoelectron microscopy, and differential gene expression analysis using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and cDNA expression array assays.


RESULTS
The TGF-beta 1-induced myofibroblastic conversion was a transdifferentiation process resulting in characteristic myofibroblastic phenotype that included prominent rough endoplasmic reticuli (rER) with dilated cisternas, conspicuous smooth muscle actin (SMA) myofilaments, frequent intercellular intermediate and gap junctions, and active deposition of extracellular matrix (ECM) and formation of fibronexus. The gene expression array analysis revealed complex modulation of gene expression involving cytoskeletal organization, cell adhesion, ECM production, cell proliferation, innate immunity, cytokine/growth factor signaling, cytoprotection, stress response, and many other essential metabolic processes in mesothelial cells.


CONCLUSIONS
This report describes myofibroblastic conversion of mesothelial cells, a previously undefined, yet frequently speculated, cell adaptive or pathogenic process. Our study helps to elucidate the complex molecular and cellular events involved in myofibroblastic conversion of mesothelial cells. We propose that differentiated epithelial cells of mesothelium convert or transdifferentiate into myofibroblasts, which implies the recruitment of fibrogenic cells from mesothelium during serosal inflammation and wound healing.
Yang
An Hang
AH
Department of Pathology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan. ahyang@vghtpe.gov.tw
Chen
Jinn Yang
JY
Lin
Jen Kou
JK
D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D017629:Gap Junctions / Q000648:ultrastructure; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008854:Microscopy, Electron; D008871:Microvilli / Q000648:ultrastructure; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010537:Peritoneum / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1