Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury
Journal
Journal of the American Society of Nephrology : JASN
Journal Volume
25
Journal Issue
12
Pages
2847
Date Issued
2014-12
Author(s)
Yeh, Pei-Ying
Liu, Yuan-Hung
Duffield, Jeremy S
Abstract
Fibrosis of the peritoneal cavity remains a serious, life-threatening problem in the treatment of kidney failure with peritoneal dialysis. The mechanism of fibrosis remains unclear partly because the fibrogenic cells have not been identified with certainty. Recent studies have proposed mesothelial cells to be an important source of myofibroblasts through the epithelial-mesenchymal transition; however, confirmatory studies in vivo are lacking. Here, we show by inducible genetic fate mapping that type I collagen-producing submesothelial fibroblasts are specific progenitors of α-smooth muscle actin-positive myofibroblasts that accumulate progressively in models of peritoneal fibrosis induced by sodium hypochlorite, hyperglycemic dialysis solutions, or TGF-β1. Similar genetic mapping of Wilms' tumor-1-positive mesothelial cells indicated that peritoneal membrane disruption is repaired and replaced by surviving mesothelial cells in peritoneal injury, and not by submesothelial fibroblasts. Although primary cultures of mesothelial cells or submesothelial fibroblasts each expressed α-smooth muscle actin under the influence of TGF-β1, only submesothelial fibroblasts expressed α-smooth muscle actin after induction of peritoneal fibrosis in mice. Furthermore, pharmacologic inhibition of the PDGF receptor, which is expressed by submesothelial fibroblasts but not mesothelial cells, attenuated the peritoneal fibrosis but not the remesothelialization induced by hypochlorite. Thus, our data identify distinctive fates for injured mesothelial cells and submesothelial fibroblasts during peritoneal injury and fibrosis.
Subjects
GROWTH-FACTOR-BETA; PERICYTE-MYOFIBROBLAST TRANSITION; TO-MESENCHYMAL TRANSITION; HEPATIC STELLATE CELLS; PULMONARY-FIBROSIS; EPITHELIAL-CELLS; KIDNEY FIBROSIS; GENE-EXPRESSION; IN-VITRO; DIALYSIS
Publisher
AMER SOC NEPHROLOGY
Type
journal article