Experimental systems to study the origin of the myofibroblast in peritoneal fibrosis

Abstract

Peritoneal fibrosis is one of the major complications occurring in long-term peritoneal dialysis patients as a result of injury. Peritoneal fibrosis is characterized by submesothelial thickening and fibrosis which is associated with a decline in peritoneal membrane function. The myofibroblast has been identified as the key player involved in the development and progression of peritoneal fibrosis. Activation of the myofibroblast is correlated with expansion of the extracellular matrix and changes in peritoneal membrane integrity. Over the years, epithelial to mesenchymal transition (EMT) has been accepted as the predominant source of the myofibroblast. Peritoneal mesothelial cells have been described to undergo EMT in response to injury. Several animal and in vitro studies support the role of EMT in peritoneal fibrosis; however, emerging evidence from genetic fate-mapping studies has demonstrated that myofibroblasts may be arising from resident fibroblasts and pericytes/perivascular fibroblasts. In this review, we will discuss hypotheses currently surrounding the origin of the myofibroblast and highlight the experimental systems predominantly being used to investigate this.

Targeting Src attenuates peritoneal fibrosis and inhibits the epithelial to mesenchymal transition

“…Peritoneal mesothelial cells have been reported to undergo epithelial-mesenchymal transition (EMT) in response to injury, a cellular event associated with peritoneal fibrosis [ 38 ]. To understand the role of Src in the EMT of peritoneal mesothelial cells, normally cultured human peritoneal mesothelial cells (HPMCs) were exposed to different doses of KX2-391 and expression of, α-SMA, fibronectin and collagen 1 were examined.…”

“…Currently, the mechanism of Src mediated peritoneal fibrosis is not fully understood. As the TGF-β/Smad3 signaling pathway has been reported to be implicated in the pathogenesis of peritoneal fibrosis [ 37 , 38 ], we examined the effect of Src inhibition on the activation of this pathway. Our results show that the CG-injured fibrotic peritoneum is accompanied by increased expression of TGF-β receptor I and II as well as phosphorylation of Smad3, a key mediator of TGF-β signaling.…”

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

“…Due to their mesodermal origin, MCs have in basal conditions an epithelial-like morphology co-expressing epithelial and mesenchymal markers, such as E-cadherin, cytokeratins, vimentin and desmin 20 . Once stimulated by TGFβ1 often in combination with TLR ligands, MCs undergo MMT and may became indistinguishable from myofibroblasts obtained from other sources 26 .…”

Tanshinone IIA mitigates peritoneal fibrosis by inhibiting EMT via regulation of TGF-β/smad pathway

“…This has been demonstrated by using adenovirus to introduce TGF-β1 into the peritoneum so as to overexpress TGF-β1, thereby inducing EMT of HPMCs and peritoneal fibrosis [25]. Bone morphogenetic protein reverses HPMC transition by inhibiting smad2/3 and MAPKs resulting from hyperglycemia-activated TGF-β1.…”