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Functional Proteome analysis of the molecular mechanism of (myo)fibroblast differentiation

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Author

Summary, in English

Tissue remodeling is observed in several physiological conditions such as embryogenesis, senescence, wound healing and pregnancy, as well as in several pathological conditions such as fibrosis and tumorgenesis. Fibroblasts play a key role in this tissue remodeling due to their capability of altering the turnover of the extracellular matrix. During the remodeling process, the fibroblasts are believed to differentiate into fibroblast-smooth muscle-like cells called myofibroblasts. This differentiation process is mediated by a well-orchestrated interplay between the extracellular matrix and growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta ). In this thesis, the overall aim was to investigate the mechanism for fibroblast activation by employing various proteomic technologies. We present a mechanistic explanation as to how TGF-beta induces alternative splicing of a number of extracellular matrix components that have been found to be essential for the differentiation process. This thesis also shows how specific carbohydrate moieties can modulate the PDGF-induced cellular response. By isolating fibroblast populations from different bronchial locations, the in vitro results could be compared with the bronchial-derived fibroblast populations by proteome profiling. To achieve these goals, application of a number of proteomic tools was necessary such as two-dimensional gel electrophoresis, multidimensional chromatography and mass spectrometers utilizing both laser desorption and electrospray ionization. A database was also constructed to store and analyze the data derived from the studies. In summary, the results showed that myofibroblast differentiation was dependent upon a coordinate interplay between the extracellular matrix components and growth factors. These growth factors act locally on the fibroblasts to induce a tissue remodeling similar to that observed in diseases such as asthma.

Publishing year

2003

Language

English

Document type

Dissertation

Publisher

Johan Malmström, BMC C13, 221 84 Lund,

Topic

  • Cell and Molecular Biology

Keywords

  • fibroblast/myofibroblast/extracellular matrix/asthma/COPD/PDGF/TGF-beta/heparan sulfate/proteoglycans/proteomics/mass spectrometry/MALDI/ESI
  • Metabolism
  • Biochemistry
  • Biokemi
  • metabolism

Status

Published

Supervisor

  • [unknown] [unknown]

ISBN/ISSN/Other

  • ISBN: 91-628-5816-5

Defence date

3 October 2003

Defence time

09:15

Defence place

GK salen, BMC

Opponent

  • Per Andrén (Dr)