Evidence that fibroblasts derive from epithelium during tissue fibrosis

Iwano, Masayuki; Plieth, David; Danoff, Theodore M.; Xue, Chengsen; Okada, Hirokazu; Neilson, Eric G.

doi:10.1172/jci15518

Cited by 1,185 publications

(1,091 citation statements)

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“…This process has been particularly studied in renal fibrosis. It has been hypothesized that when basement membrane is injured by matrix metaroproteinase, epithelial cells that detach from their basement membrane may enter into epithelial-mesenchymal transition, express HSP47 and other mesenchymal markers and divide as fibroblasts [33][34][35]. Whether this process takes place in the lung in IPF or in other forms of pulmonary fibrosis is largely unknown, but urgent evaluation in vitro and in vivo would be necessary.…”

Section: Discussionmentioning

confidence: 99%

Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis

et al. 2010

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Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that has been shown to play a major role in the processing and/or secretion of procollagen. However, the knowledge on which cells are actually synthesizing HSP47 in the lung parenchyma in pulmonary fibrosis was only limited. The aim of the present study was to investigate the localization of HSP47 messenger ribonucleic acid (mRNA) in normal lung, and in the lungs of mice in bleomycin-induced pulmonary fibrosis, using in situ hybridization.For the purpose, ICR mice were intravenously injected with 10 mg/kg/day of bleomycin for 5 consecutive days. The lung cells expressing HSP47 mRNA were identified in control (saline alone) and bleomycin-treated mice by in situ hybridization. The signal for HSP47 mRNA was markedly increased in bleomycin-treated lungs compared with that of controls. HSP47 mRNA was localized in -smooth muscle actin-positive myofibroblasts, surfactant protein A-positive type II pneumocytes and F4/80 positive macrophages in the active fibrotic areas. These results suggest that these cells may synthesize procollagen in the fibrotic process of bleomycin-treated lungs through upregulation of HSP47 mRNA and play an important role in fibrogenesis.

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Section: Discussionmentioning

confidence: 99%

Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis

et al. 2010

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“…6 During this process tubule cells loose epithelial features and convert to fibroblast-like cells. 3 This epithelial-mesenchymal transition (EMT) is paralleled for example by the expression of fibroblast-specific protein-1(FSP1), 13 heat shock protein 47 (HSP 47) 10,16,21 and a-smooth muscle actin (SMA). 31 In contrast, mesenchymal-epithelial transition (MET) plays an important role, when stem/progenitor cells are applied to support regeneration in acute or chronic renal failure.…”

Section: Discussionmentioning

confidence: 99%

The Interface Between Generating Renal Tubules and a Polyester Fleece in Comparison to the Interstitium of the Developing Kidney

et al. 2010

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Abstract-An increasing number of investigations is dealing with the repair of acute and chronic renal failure by the application of stem/progenitor cells. However, accurate data concerning the cell biological mechanisms controlling the process of regeneration are scarce. For that reason new implantation techniques, advanced biomaterials and morphogens supporting regeneration of renal parenchyma are under research. Special focus is directed to structural and functional features of the interface between generating tubules and the surrounding interstitial space. The aim of the present experiments was to investigate structural features of the interstitium during generation of tubules. Stem/ progenitor cells were isolated from neonatal rabbit kidney and mounted between layers of a polyester fleece to create an artificial interstitium. Perfusion culture was performed for 13 days in chemically defined Iscove's Modified Dulbecco's Medium containing aldosterone (1 9 10 À7 M) as tubulogenic factor. Recordings of the artificial interstitium in comparison to the developing kidney were performed by morphometric analysis, scanning and transmission electron microscopy. The degree of differentiation was registered by immunohistochemistry. The data reveal that generated tubules are embedded in a complex network of fibers consisting of newly synthesized extracellular matrix proteins. Morphometric analysis further shows that the majority of tubules within the artificial interstitium develops in a surprisingly close distance between 5 and 25 lm to each other. The abundance of synthesized extracellular matrix acts obviously as a spacer keeping generated tubules in distance. For comparison, the same principle of construction is found in the developing parenchyma of the neonatal kidney. Most astonishingly, scanning electron microscopy reveals that the composition of interstitial matrix is not homogeneous but differs along a cortico-medullary axis of proceeding tubule development.Keywords-Tissue engineering, Perfusion culture, Kidney, Tubule, Artificial interstitium, Collagen type III. INTRODUCTIONRecovery from renal failure requires the replacement of injured tissue with new cells that restore epithelial integrity and functionality within tubules. An increasing number of papers is therefore dealing with strategies for repair of parenchyma by the help of stem/progenitor cells. 5,12 However, recent data show that an effective therapy is still far away from a widespread clinic application. Unsolved issues in renal tissue engineering are the concentration of stem/progenitor cells at the site of damage, their integration in a diseased environment, the process of differentiation into nephron-specific cells, and the spatial development of tubules within the kidney. 32 Part of actual research is focusing on cell biological mechanisms involved in the formation of tubules during regeneration. 4 Due to the spatial microarchitecture of the kidney experiments are frequently performed applying three-dimensional culture experiments in combination wi...

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“…However, recent studies have shown that epithelial cells contribute to fibroblast accumulation through an epithelial-mesenchymal transition (EMT) in the kidney, lung, and liver, in addition to the proliferation of resident fibroblasts and bone marrow-derived fibroblasts [6]. Experiments in mice have demonstrated that endothelial cells associated with the microvasculature can also contribute to the formation of mesenchymal cells during the course of fibrosis via a similar process known as endothelial-mesenchymal transition (EndMT) [7].…”

Section: Introductionmentioning

confidence: 99%