Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury.
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.
Graduate Institute of Physiology, College of Medicine, and Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan;
Yi-Ting
YT
Chen
Graduate Institute of Physiology, College of Medicine, and.
Yu-Ting
YT
Chang
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Szu-Yu
SY
Pan
Graduate Institute of Physiology, College of Medicine, and Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Yu-Hsiang
YH
Chou
Graduate Institute of Physiology, College of Medicine, and Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Fan-Chi
FC
Chang
Graduate Institute of Physiology, College of Medicine, and.
Pei-Ying
PY
Yeh
Department of Cardiovascular Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; and.
Yuan-Hung
YH
Liu
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Wen-Chih
WC
Chiang
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Yung-Ming
YM
Chen
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Kwan-Dun
KD
Wu
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan;
Tun-Jun
TJ
Tsai
Institute for Stem Cell and Regenerative Medicine, and Kidney Research Institute, University of Washington, Seattle, Washington.
Jeremy S
JS
Duffield
Graduate Institute of Physiology, College of Medicine, and Renal Division, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan; linsl@ntu.edu.tw.
Shuei-Liong
SL
Lin
D000818:Animals; D019070:Cell Lineage; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D017930:Genes, Reporter; D005819:Genetic Markers / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006997:Hypochlorous Acid / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D056627:Peritoneal Fibrosis / Q000473:pathology; D010537:Peritoneum / Q000473:pathology*; D013629:Tamoxifen / Q000737:chemistry; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005819:Genetic Markers; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D006997:Hypochlorous Acid