Mechanisms and Kinetics of Bowman’s Epithelial-Myofibroblast Transdifferentiation in the Formation of Glomerular Crescents

Abstract

Background: We investigated the mechanisms and kinetics of Bowman’s epithelial-myofibroblast transdifferentiation in the formation of glomerular crescents. Methods: Crescentic glomerulonephritis was induced by i.v. injection of rabbit anti-rat glomerular basement membrane antiserum in WKY rats. Results: Cellular crescents (83.5% of glomeruli) were first observed at day 7 after disease induction. Immunostaining of alpha-smooth muscle actin (alpha-SMA), as a marker for the myofibroblast phenotype, was found in some periglomerular regions as early as day 3, when it was also seen in parietal epithelial cells (PEC) of Bowman’s capsule at day 5 and in crescent formation at day 7. Proliferation marker Ki67-positive PEC was found at day 3, and double Ki67- and alpha-SMA-positive PEC could be seen at day 5. The migratory figure of PEC with the expression of alpha-SMA was found by immunoelectron microscopy. At day 7, some crescent cells were stained positive for PEC marker, protein gene product 9.5, in association with alpha-SMA or Ki67. Expression of transforming growth factor (TGF)-β receptor types I and II, as well as platelet-derived growth factor (PDGF) receptor β and PDGF-B increased in PEC as early as day 3. At day 5 marked deposition of cellular and common fibronectin, but not other extracellular matrix components examined was found in Bowman’s spaces where ED 1-positive macrophages infiltrated. Conclusions: PEC may be stimulated to proliferate and/or transdifferentiate into myofibroblast phenotype possibly by action of TGF-β and PDGF and/or binding of fibronectin to PEC, then migrate and/or proliferate, participating in glomerular crescents.

Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland

“…Thus, toxic or pathological stimuli and͞or the presence of stem cells may explain the appearance of hepatocytes in the rodent pancreas in response to a copper-deficient diet (24,25) or insular overexpression of keratinocyte growth factor (26). Similar mechanisms may be responsible for transdifferentiation of hepatic to exocrine pancreatic cells after treatment with polychlorinated biphenils (27) and transplantation of pancreatic epithelial cells (28), as well as for the conversion of kidney tubular epithelial cells into fibroblasts during experimental fibrosis (29) and of Bowman's capsule epithelial cells into myofibroblasts during experimental glomerulonephritis (30). On the other hand, the term ''transdifferentiation'' can hardly be applied to the differentiation of embryonic endothelial cells into cardiomyocytes in various experimental conditions (31) or to the switch from muscular to adipose phenotype in skeletal muscle under disruption of Wnt signaling (32).…”

Establishment of Conditionally Immortalized Mouse Glomerular Parietal Epithelial Cells in Culture

“…Isolated glomeruli were plated onto type I collagen-coated 10-cm plates (at a concentration of 6 glomeruli/cm 2 ) and maintained in medium containing 5% FBS. Cellular outgrowths were observed daily by an inverted light microscope.…”

“…PEC make up a large part of glomerular crescents in certain forms of ANCA and non-ANCA-related glomerulonephritis. Moreover, in disease, they express several cytokines and chemokines, such as TGF-␤1, 1 PDGF-B, 2 and CTGF, 3 and more recent studies suggested that they might also be precursors to podocytes. 4 Several animal models of glomerulonephritis characterized by PEC proliferation have enhanced our understanding of these cells in disease.…”

Fibroblast Phenotype Plasticity: Relevance for Understanding Heterogeneity in “Fibroblastic” Tumors

“…These changes are often referred to as cellular transformation or transdifferentiation, and reflect cell-type phenotypic plasticity. Phenotypic plasticity is also observed or has been postulated in pathological tissues [5,6], including neoplastic disease [5]. Here, within any given tumor-type (for example, lymphoma, carcinoma, melanoma, sarcoma) we are aware that a diversity of differentiation is often found, and this can also be regarded as an expression of phenotypic plasticity.…”