Fibrotic response in fibroblasts from congenital disorders of glycosylation

Abstract

Congenital disorders of glycosylation (CDG) are characterized by a generalized underglycosylation of proteins. CDG is associated with multiple symptoms such as psychomotor retardation, hypotonia, hormonal disturbances, liver fibrosis and coagulopathies. The molecular basis of these symptoms is poorly understood considering the large extent of affected glycoproteins. To better understand the cellular responses to protein underglycosylation in CDG, we have investigated the differences in gene expression between healthy control and CDG fibroblasts by transcriptome comparison. This analysis revealed a strong induction of several genes encoding components of the extracellular matrix, such as collagens, COMP, IGFBP5 and biglycan. The extent of this response was confirmed at the protein level by showing increased production of collagen type-I for example. This fibrotic response of CDG fibroblasts was not paralleled by a differentiation to myofibroblasts and by increased TGF-β signalling. We could show that the addition of recombinant IGFBP5, one of the induced proteins in CDG, to healthy control fibroblasts increased the production of collagen type-I to levels similar to those found in CDG fibroblasts. The fibrotic response identified in CDG fibroblasts may account for the elevated tissue fibrosis, which is often encountered in CDG patients.

Sustained β‐catenin activity in dermal fibroblasts promotes fibrosis by up‐regulating expression of extracellular matrix protein‐coding genes

“…Our result contrasts with the increase of α SMA + cells reported in the skin of mice with post‐natal induction of stabilized β ‐catenin expression in fibroblasts, suggesting that the age or identity of resident dermal fibroblasts may affect the appearance of α SMA + cells in skin fibrosis . Myofibroblasts are well documented in fibrosis but not universally present during pathological fibrosis . Our findings show that, in clinical fibrosis, β ‐catenin signalling in dermal fibroblasts is likely a downstream event from the involvement of these other cell types.…”

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

“…Previously published transcriptomic analysis of fibroblasts from multiple CDGs demonstrated increased expression of genes encoding ECM proteins compared to control fibroblasts . Consistent with these data, our transcriptomic analysis of low‐ MPI human liver fibrosis samples and MPI‐depleted HSC and zebrafish liver tissues demonstrated similar affected genes and pathways.…”

Skin manifestations in CDG

“…In 2010, Lecca et al compared gene expression profiles in healthy control and CDG type I fibroblasts, demonstrating an important induction of genes encoding extracellular matrix proteins. These findings were confirmed at the protein level showing an increased production of collagen-I by patient fibroblasts (Lecca et al 2011). Thus, this pro-fibrotic tissue response could explain the occurrence of orange peel skin in certain CDG type I patients.…”