title: Involvement of hyaluronan in regulation of fibroblast phenotype.
abstract: This study aimed to understand the role of the matrix polysaccharide, hyaluronan (HA), in influencing the scarring process by assessing its impact on regulating fibroblast behavior. Donor-matched human oral and dermal fibroblasts were used as models of nonscarring and scarring fibroblast phenotypes, respectively. Phenotypic differences in these two fibroblast populations were assessed and related to differences in HA synthesis and assembly. The two fibroblast populations showed intrinsic differences in their response to the profibrotic cytokine, transforming growth factor-beta1 (TGFbeta1), in that oral fibroblasts were resistant to TGFbeta1-driven myofibroblastic differentiation. In dermal fibroblasts, differentiation was associated with an induction of HA synthase (HAS1 and HAS2) transcription and assembly of pericellular HA coats. In comparison, resistance to differentiation in oral fibroblasts was associated with failure of induction of HAS1 and HAS2 transcription and failure of pericellular coat assembly. Furthermore, inhibition of HA synthesis in dermal fibroblasts significantly attenuated TGFbeta1-mediated differentiation. Interleukin-1beta stimulation resulted in induction of HAS1 and HAS2 transcription but did not induce phenotypic differentiation or induce HA coat assembly. In addition, neither overexpression nor down-regulation of HAS1 (the isoform uniquely deficient in nonscarring oral fibroblasts) influenced phenotypic differentiation. In conclusion, inhibiting HA synthesis modulates TGFbeta1-dependent responses in these cells preventing fibroblast to myofibroblast differentiation. Moreover, HA pericellular coat assembly, rather than HAS isoform expression, appears to be associated with phenotypic differentiation.
authors.affiliation: Institute of Nephrology, School of Medicine, and Department of Oral Surgery, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Soma
authors.initials: S
authors.lastname: Meran
authors.forename: David
authors.initials: D
authors.lastname: Thomas
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Timothy
authors.initials: T
authors.lastname: Bowen
authors.forename: Aled
authors.initials: A
authors.lastname: Phillips
authors.forename: Robert
authors.initials: R
authors.lastname: Steadman
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002921:Cicatrix / Q000201:enzymology; D020405:Dermis / Q000166:cytology / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009061:Mouth Mucosa / Q000166:cytology / Q000201:enzymology*; D009928:Organ Specificity / Q000502:physiology; D010641:Phenotype; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D007527:Isoenzymes; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases