Project title
命運追蹤間皮細胞與腹膜間皮下基質細胞在腹膜纖維化與修復的角色
Internal ID
NSC102-2628-B002-015-MY3
Principal Investigator
Start Date
August 1, 2013
End Date
July 12, 2014
Investigators
Organizations
Partner Organizations
Project Web Site
Fate Trace the Role of Mesothelial Cells and Submesothelilal Stromal Cells in Peritoneal Fibrosis and Repair = 命運追蹤間皮細胞與腹膜間皮下基質細胞在腹膜纖維化與修復的角色
Keywords
腹膜透析
腹膜間皮細胞
腹膜間皮下基質母細胞
腹膜纖維化
祖細胞
peritoneal dialysis
mesothelial cells
submesothelial stromal cells
peritoneal fibrosis
progenitor cell
Description
Peritoneal dialysis (PD) is a life-sustaining therapy used by > 100,000 patients with end-stage renal disease worldwide, accounting for approximately 10 to 15% of the dialysis population. One of the major obstacles to successful long-term PD is deleterious functional alteration in the peritoneal membrane after exposure to dialysis solutions; this loss of dialysis capacity is responsible for increased morbidity and mortality. These alterations, involving approximately 50% of all PD patients, include progressive fibrosis, angiogenesis, and vascular degeneration associated with increased solute transport and loss of ultrafiltration. In a small percentage of cases, a poorly defined but catastrophic fibrogenic response occurs primarily in the visceral peritoneum, leading to the onset of encapsulating peritoneal sclerosis (EPS) with an associated high mortality rate. Although advances in new dialysis solutions and connection systems improve the biocompatibility and reduce the incidence of peritonitis, membrane failure due to progressive fibrosis remains a big problem. There is thus a growing need to understand the molecular basis of these membrane-degenerative events and a need to improve the regeneration of injured peritoneum. Peritoneum is basically composed of mesothelial cells, submesothelial stromal cells and extracellular matrix. It is highly controversial about the origin of peritoneal myofibroblasts responsible for the progressive fibrosis and whether there are progenitor cells to regenerate injured mesothelium. The popular hypothesis that mesothelial cells contribute to the most peritoneal myofibroblasts through epithelial-mesenchymal transition is proposed based on the immunohistochemical staining. This hypothesis lacks direct evidence in vivo. We have recently used the genetically engineered mice to study the origin of regenerated tubular epithelial cells in acute kidney injury and interstitial myofibroblasts in chronic progressive kidney fibrosis. We have clearly shown that the regeneration by surviving tubular epithelial cells is the predominant mechanism of repair after ischemic tubular injury and the origin of interstitial myofibroblasts are pericytes, not from epithelial-mesenchymal transition of injured tubular epithelial cells. In this study we will first use the green reporter mice whose GFP is driven by collagen I (α1) promoter to study the collagen producing cells in normal and injured peritoneum. We will then use cell-specific and time-specific genetically fluorescence-labelled mesothelial cells and submesothelial stromal cells to trace the origin of the collagen-producing cells and regenerated mesothelial cells in injured peritoneum. Bone marrow chimeric mice with bone marrow from different reporter mice will help us clarify the role of bone marrow derived cells in the peritoneal myofibroblasts and regenerated mesothelial cells. This state-of-the-art and most reliable fate-tracing technique will lead us to understand the origin of both peritoneal myofibroblasts and progenitor cells to repair injured mesothelium. We will next study the evolution of transcriptomes of mesothelial and submesothelial stromal cells during peritoneal injury by microarray analyses that will unravel novel targets for prevention of peritoneal fibrosis and promotion of mesothelial regeneration. We will further study the role of Wilms’ tumor 1 in the peritoneal fibrosis by conditional knock out in submesothelial stromal cells. Through this study we may advance our knowledge how to maintain the healthy mesothelial cell mass and specifically prevent the formation of pathological myofibroblasts. The results may also help the development of prevention and therapy for adhesion after abdominal surgery.