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J. Biol. Chem., Vol. 283, Issue 10, 6530-6545, March 7, 2008

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Hyaluronan Facilitates Transforming Growth Factor-β₁-mediated Fibroblast Proliferation^*

Soma Meran, David W. Thomas, Phillip Stephens, Stuart Enoch, John Martin, Robert Steadman¹, and Aled O. Phillips¹²

From the Institute of Nephrology, School of Medicine, and the 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 aims to understand the role of the matrix polysaccharide hyaluronan (HA) in influencing fibroblast proliferation and thereby affecting wound healing outcomes. To determine mechanisms that underlie scarred versus scar-free healing, patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non-scarring fibroblast phenotypes. Specifically, differences in HA generation between these distinct fibroblast populations have been examined and related to differences in transforming growth factor-β₁ (TGF-β₁)-dependent proliferative responses and Smad signaling. There was a differential growth response to TGF-β₁, with it inducing proliferation in dermal fibroblasts but an anti-proliferative response in oral fibroblasts. Both responses were Smad3-dependent. Furthermore, the two fibroblast populations also demonstrated differences in their HA regulation, with dermal fibroblasts generating increased levels of HA, compared with oral fibroblasts. Inhibition of HA synthesis in dermal fibroblasts was shown to abrogate the TGF-β₁-mediated induction of proliferation. Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts. Microarray analysis demonstrated no difference in the genes involved in TGF-β₁ signaling between dermal and oral fibroblasts, whereas there was a distinct difference in the pattern of genes involved in HA regulation. In conclusion, these two distinct fibroblast populations demonstrate a differential proliferative response to TGF-β₁, which is associated with differences in HA generation. TGF-β₁ regulates proliferation through Smad3 signaling in both fibroblast populations; however, it is the levels of HA generated by the cells that influence the outcome of this response.

Received for publication, June 12, 2007 , and in revised form, December 18, 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: phillipsao{at}cf.ac.uk.

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This article has been cited by other articles:

				J. Webber, R. H. Jenkins, S. Meran, A. Phillips, and R. Steadman Modulation of TGF{beta}1-Dependent Myofibroblast Differentiation by Hyaluronan Am. J. Pathol., July 1, 2009; 175(1): 148 - 160. [Abstract] [Full Text] [PDF]

				J. Webber, S. Meran, R. Steadman, and A. Phillips Hyaluronan Orchestrates Transforming Growth Factor-{beta}1-dependent Maintenance of Myofibroblast Phenotype J. Biol. Chem., April 3, 2009; 284(14): 9083 - 9092. [Abstract] [Full Text] [PDF]