Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation

Yee Yung Ng, Jun Ming Fan, Wei Mu, David J. Nikolic-Paterson, Wu Chang Yang, Tung Po Huang, Robert C. Atkins, Hui Y. Lan

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Abstract

Background. Glomerular cellular crescents consist of epithelial cells and macrophages, which can undergo an irreversible process of fibrous organization. However, the origin of the fibroblast-type cells that mediate this fibrous organization is unclear. Methods. This study examined glomerular epithelial-myofibroblast transdifferentiation (GEMT) in the formation and evolution of glomerular crescents in two distinct rat models of glomerulonephritis: 5/6 nephrectomy and antiglomerular basement membrane (GBM) disease. Results. Early in the course of both disease models, and prior to crescent formation, immunohistochemistry staining and in-situ hybridization demonstrated de novo expression of alpha-smooth-muscle actin (α-SMA), a marker of smooth muscle cells and myofibroblasts, by glomerular parietal epithelial cells (GPEC). The expression of α-SMA by GPEC was accompanied by a loss of E-cadherin staining, a marker of epithelial cells. At this early stage of GEMT, ultrastructural studies identified the presence of characteristic actin microfilaments and dense bodies within GPEC which retained a normal epithelial morphology with apical-basal polarity and microvilli. A late stage of transdifferentiation was seen in fibrocellular crescents. In this case, GPEC attached to intact segments of the capsular basement membrane contained large bundles of actin microfilaments throughout the cell, and this was accompanied by a loss of polarity, microvilli, and tight junctions. There was a significant correlation between the presence of α-SMA+ GPEC and glomerular crescent formation. Cellular crescents contained small numbers of α-SMA+ myofibroblasts. These cells become the dominant population in fibrocellular crescents, which was associated with marked local proliferation. Relatively few α-SMA+ myofibroblasts remained in fibrotic/organizing crescents. Most cells within cellular and fibrocellular crescents expressed transforming growth factor-β (TGF-β) and basic fibroblast growth factor (FGF-2), suggesting that these growth factors may regulate this GEMT process during the evolution of glomerular crescents. Conclusions. This study provides the first phenotypic and morphological evidence that glomerular epithelial-myofibroblast transdifferentiation participates in the formation and evolution of glomerular crescents.

Original languageEnglish
Pages (from-to)2860-2872
Number of pages13
JournalNephrology Dialysis Transplantation
Volume14
Issue number12
DOIs
Publication statusPublished - 1 Jan 1999

Keywords

  • Glomerular crescents
  • Glomerular epithelial cells
  • Glomerulonephritis
  • Myofibroblasts
  • Transdifferentiation

Cite this

Ng, Yee Yung ; Fan, Jun Ming ; Mu, Wei ; Nikolic-Paterson, David J. ; Yang, Wu Chang ; Huang, Tung Po ; Atkins, Robert C. ; Lan, Hui Y. / Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. In: Nephrology Dialysis Transplantation. 1999 ; Vol. 14, No. 12. pp. 2860-2872.
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title = "Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation",
abstract = "Background. Glomerular cellular crescents consist of epithelial cells and macrophages, which can undergo an irreversible process of fibrous organization. However, the origin of the fibroblast-type cells that mediate this fibrous organization is unclear. Methods. This study examined glomerular epithelial-myofibroblast transdifferentiation (GEMT) in the formation and evolution of glomerular crescents in two distinct rat models of glomerulonephritis: 5/6 nephrectomy and antiglomerular basement membrane (GBM) disease. Results. Early in the course of both disease models, and prior to crescent formation, immunohistochemistry staining and in-situ hybridization demonstrated de novo expression of alpha-smooth-muscle actin (α-SMA), a marker of smooth muscle cells and myofibroblasts, by glomerular parietal epithelial cells (GPEC). The expression of α-SMA by GPEC was accompanied by a loss of E-cadherin staining, a marker of epithelial cells. At this early stage of GEMT, ultrastructural studies identified the presence of characteristic actin microfilaments and dense bodies within GPEC which retained a normal epithelial morphology with apical-basal polarity and microvilli. A late stage of transdifferentiation was seen in fibrocellular crescents. In this case, GPEC attached to intact segments of the capsular basement membrane contained large bundles of actin microfilaments throughout the cell, and this was accompanied by a loss of polarity, microvilli, and tight junctions. There was a significant correlation between the presence of α-SMA+ GPEC and glomerular crescent formation. Cellular crescents contained small numbers of α-SMA+ myofibroblasts. These cells become the dominant population in fibrocellular crescents, which was associated with marked local proliferation. Relatively few α-SMA+ myofibroblasts remained in fibrotic/organizing crescents. Most cells within cellular and fibrocellular crescents expressed transforming growth factor-β (TGF-β) and basic fibroblast growth factor (FGF-2), suggesting that these growth factors may regulate this GEMT process during the evolution of glomerular crescents. Conclusions. This study provides the first phenotypic and morphological evidence that glomerular epithelial-myofibroblast transdifferentiation participates in the formation and evolution of glomerular crescents.",
keywords = "Glomerular crescents, Glomerular epithelial cells, Glomerulonephritis, Myofibroblasts, Transdifferentiation",
author = "Ng, {Yee Yung} and Fan, {Jun Ming} and Wei Mu and Nikolic-Paterson, {David J.} and Yang, {Wu Chang} and Huang, {Tung Po} and Atkins, {Robert C.} and Lan, {Hui Y.}",
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Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. / Ng, Yee Yung; Fan, Jun Ming; Mu, Wei; Nikolic-Paterson, David J.; Yang, Wu Chang; Huang, Tung Po; Atkins, Robert C.; Lan, Hui Y.

In: Nephrology Dialysis Transplantation, Vol. 14, No. 12, 01.01.1999, p. 2860-2872.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation

AU - Ng, Yee Yung

AU - Fan, Jun Ming

AU - Mu, Wei

AU - Nikolic-Paterson, David J.

AU - Yang, Wu Chang

AU - Huang, Tung Po

AU - Atkins, Robert C.

AU - Lan, Hui Y.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - Background. Glomerular cellular crescents consist of epithelial cells and macrophages, which can undergo an irreversible process of fibrous organization. However, the origin of the fibroblast-type cells that mediate this fibrous organization is unclear. Methods. This study examined glomerular epithelial-myofibroblast transdifferentiation (GEMT) in the formation and evolution of glomerular crescents in two distinct rat models of glomerulonephritis: 5/6 nephrectomy and antiglomerular basement membrane (GBM) disease. Results. Early in the course of both disease models, and prior to crescent formation, immunohistochemistry staining and in-situ hybridization demonstrated de novo expression of alpha-smooth-muscle actin (α-SMA), a marker of smooth muscle cells and myofibroblasts, by glomerular parietal epithelial cells (GPEC). The expression of α-SMA by GPEC was accompanied by a loss of E-cadherin staining, a marker of epithelial cells. At this early stage of GEMT, ultrastructural studies identified the presence of characteristic actin microfilaments and dense bodies within GPEC which retained a normal epithelial morphology with apical-basal polarity and microvilli. A late stage of transdifferentiation was seen in fibrocellular crescents. In this case, GPEC attached to intact segments of the capsular basement membrane contained large bundles of actin microfilaments throughout the cell, and this was accompanied by a loss of polarity, microvilli, and tight junctions. There was a significant correlation between the presence of α-SMA+ GPEC and glomerular crescent formation. Cellular crescents contained small numbers of α-SMA+ myofibroblasts. These cells become the dominant population in fibrocellular crescents, which was associated with marked local proliferation. Relatively few α-SMA+ myofibroblasts remained in fibrotic/organizing crescents. Most cells within cellular and fibrocellular crescents expressed transforming growth factor-β (TGF-β) and basic fibroblast growth factor (FGF-2), suggesting that these growth factors may regulate this GEMT process during the evolution of glomerular crescents. Conclusions. This study provides the first phenotypic and morphological evidence that glomerular epithelial-myofibroblast transdifferentiation participates in the formation and evolution of glomerular crescents.

AB - Background. Glomerular cellular crescents consist of epithelial cells and macrophages, which can undergo an irreversible process of fibrous organization. However, the origin of the fibroblast-type cells that mediate this fibrous organization is unclear. Methods. This study examined glomerular epithelial-myofibroblast transdifferentiation (GEMT) in the formation and evolution of glomerular crescents in two distinct rat models of glomerulonephritis: 5/6 nephrectomy and antiglomerular basement membrane (GBM) disease. Results. Early in the course of both disease models, and prior to crescent formation, immunohistochemistry staining and in-situ hybridization demonstrated de novo expression of alpha-smooth-muscle actin (α-SMA), a marker of smooth muscle cells and myofibroblasts, by glomerular parietal epithelial cells (GPEC). The expression of α-SMA by GPEC was accompanied by a loss of E-cadherin staining, a marker of epithelial cells. At this early stage of GEMT, ultrastructural studies identified the presence of characteristic actin microfilaments and dense bodies within GPEC which retained a normal epithelial morphology with apical-basal polarity and microvilli. A late stage of transdifferentiation was seen in fibrocellular crescents. In this case, GPEC attached to intact segments of the capsular basement membrane contained large bundles of actin microfilaments throughout the cell, and this was accompanied by a loss of polarity, microvilli, and tight junctions. There was a significant correlation between the presence of α-SMA+ GPEC and glomerular crescent formation. Cellular crescents contained small numbers of α-SMA+ myofibroblasts. These cells become the dominant population in fibrocellular crescents, which was associated with marked local proliferation. Relatively few α-SMA+ myofibroblasts remained in fibrotic/organizing crescents. Most cells within cellular and fibrocellular crescents expressed transforming growth factor-β (TGF-β) and basic fibroblast growth factor (FGF-2), suggesting that these growth factors may regulate this GEMT process during the evolution of glomerular crescents. Conclusions. This study provides the first phenotypic and morphological evidence that glomerular epithelial-myofibroblast transdifferentiation participates in the formation and evolution of glomerular crescents.

KW - Glomerular crescents

KW - Glomerular epithelial cells

KW - Glomerulonephritis

KW - Myofibroblasts

KW - Transdifferentiation

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DO - 10.1093/ndt/14.12.2860

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SN - 0931-0509

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