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J. Biol. Chem., Vol. 282, Issue 35, 25687-25697, August 31, 2007

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Involvement of Hyaluronan in Regulation of Fibroblast Phenotype^*

Soma Meran, David Thomas, Philip Stephens, John Martin, Timothy Bowen, Aled Phillips¹, and Robert Steadman¹²

From the Institute of Nephrology, School of Medicine, and Department of Oral Surgery, School of Dentistry, Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom

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-₁ (TGF₁), in that oral fibroblasts were resistant to TGF₁-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 TGF₁-mediated differentiation. Interleukin-1 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 TGF₁-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.

Received for publication, January 26, 2007 , and in revised form, June 4, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 442920748467; Fax: 442920748470; E-mail: steadmanr{at}cf.ac.uk.

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				S. Meran, D. W. Thomas, P. Stephens, S. Enoch, J. Martin, R. Steadman, and A. O. Phillips Hyaluronan Facilitates Transforming Growth Factor-{beta}1-mediated Fibroblast Proliferation J. Biol. Chem., March 7, 2008; 283(10): 6530 - 6545. [Abstract] [Full Text] [PDF]