Lineage Tracing Reveals Distinctive Fates for Mesothelial Cells and Submesothelial Fibroblasts during Peritoneal Injury

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 a-smooth muscle actin-positive myofibroblasts that accumulate progressively in models of peritoneal fibrosis induced by sodium hypochlorite, hyperglycemic dialysis solutions, or TGF-b1. 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 a-smooth muscle actin under the influence of TGF-b1, only submesothelial fibroblasts expressed a-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.

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

“…CreERT2 or Col1a1 GFP mice, Chen et al 25 reported that the contribution of MCs to myofibroblasts is rare in the liver. By treating Wt1…”

“…In addition, they reported that MCs are negative for GFP in the Col1a1 GFP mouse liver. Chen et al 25 did not analyze the body wall in these models. In our experimental condition, we labeled 12.5% and 14.5% of MCs in the body wall and liver, respectively, in the Wt1…”

“…23e25 Sakai et al 24 reported that connective tissue growth factor (CTGF) secreted from MCs induces the proliferation and myofibroblastic conversion of fibroblasts in peritoneal fibrosis. Chen et al 25 traced liver MCs in mouse peritoneal fibrosis models and indicated that fibroblasts are the main source of myofibroblasts in liver injury. However, the origin of myofibroblasts in peritoneal fibrosis remains to be determined by rigorous cell lineage tracing.…”

Recommendations for pathological diagnosis on biopsy samples from peritoneal dialysis patients

“…Numerous studies have revealed signaling pathways of angiogenesis and fibrosis in the context of epithelial mesenchymal transition (EMT) (mesothelial cell to myofibroblast) associated with PDderived peritoneal injury (for review [67,85]). However, the primary origin of myofibroblast in PD peritoneum is argued by recent insight [86]. Otherwise, the dialysate level of connective tissue growth factor (CTGF), which inhibits bone morphogenetic protein-7 (BMP-7) and activates transforming growth factor (TGF)-β (pro-fibrosis factor), was shown be correlated to high-fast PET [87].…”

Análise do efeito do ácido valpróico no modelo experimental de fibrose peritoneal em ratos

“…Os miofibroblastos derivados do mesotélio seriam as responsáveis pela produção de colágeno e fibronectina resultando na fibrose peritoneal (28,36). No entanto, estudos in vivo não foram capazes de demonstrar esse fenômeno e recentemente, Chen YT e cols, demonstraram elegantemente que os miofibroblastos da camada submesotelial peritoneal se originam dos fibroblastos residentes predominantemente (37). A ativação desses fibroblastos resultaria na produção de fatores prófibróticos bem como no aumento da expressão VEGF que contribui para a neoangiogênese (38).…”