The differentiation of resident fibroblasts to myofibroblasts is central to wound healing. In the context of organ fibrosis, however, persistence of these myofibroblasts is associated with progressive disease. This study examines mechanisms controlling the maintenance of the myofibroblast phenotype. Myofibroblasts were induced by adding transforming growth factor-β1 (TGF-β1) (10 ng/ml) to fibroblasts for 72 h. The phenotype was maintained for up to 120 h following removal of TGF-β1. Western blot for pSmad2 and -3 demonstrated persistent phosphorylation despite removal of exogenous TGF-β1. This persistence was because of autocrine synthesis of TGF-β1, which was inhibited by both anti-TGF-β1 antibody and the ALK5 inhibitor SB431542. Persistence of phenotype was also associated with increased hyaluronan (HA) generation, synthesis of the hyaladherin TSG6, and HA pericellular coat formation. These were all inhibited by TGF-β receptor blockade. To further investigate the importance of HA synthesis, 4-methylumbelliferone was used to deplete the cytoplasmic pool of UDP-glucuronic acid, essential for HA chain elongation. This prevented formation of the pericellular HA matrix and decreased expression of α-SMA. 4-Methylumbelliferone had no effect, however, on Smad2 and -3 phosphorylation. Similarly inhibition of HAS2 by short interfering RNA prevented phenotypic activation without altering TGF-β1-dependent Smad phosphorylation, thus suggesting that HA-dependent regulation of cell phenotype was independent of Smad activation. These data suggest that myofibroblasts in areas of fibrosis maintain their own phenotype through autocrine TGF-β1 action and that extracellular HA matrices are an essential mediator of this. We propose a model in which the formation of the pericellular HA matrix regulates the outcome of Smad-dependent autocrine TGF-β1-activated signaling, and therefore persistence of the myofibroblast phenotype. The differentiation of resident fibroblasts to myofibroblasts is central to wound healing. In the context of organ fibrosis, however, persistence of these myofibroblasts is associated with progressive disease. This study examines mechanisms controlling the maintenance of the myofibroblast phenotype. Myofibroblasts were induced by adding transforming growth factor-β1 (TGF-β1) (10 ng/ml) to fibroblasts for 72 h. The phenotype was maintained for up to 120 h following removal of TGF-β1. Western blot for pSmad2 and -3 demonstrated persistent phosphorylation despite removal of exogenous TGF-β1. This persistence was because of autocrine synthesis of TGF-β1, which was inhibited by both anti-TGF-β1 antibody and the ALK5 inhibitor SB431542. Persistence of phenotype was also associated with increased hyaluronan (HA) generation, synthesis of the hyaladherin TSG6, and HA pericellular coat formation. These were all inhibited by TGF-β receptor blockade. To further investigate the importance of HA synthesis, 4-methylumbelliferone was used to deplete the cytoplasmic pool of UDP-glucuronic acid, essential for HA chain elongation. This prevented formation of the pericellular HA matrix and decreased expression of α-SMA. 4-Methylumbelliferone had no effect, however, on Smad2 and -3 phosphorylation. Similarly inhibition of HAS2 by short interfering RNA prevented phenotypic activation without altering TGF-β1-dependent Smad phosphorylation, thus suggesting that HA-dependent regulation of cell phenotype was independent of Smad activation. These data suggest that myofibroblasts in areas of fibrosis maintain their own phenotype through autocrine TGF-β1 action and that extracellular HA matrices are an essential mediator of this. We propose a model in which the formation of the pericellular HA matrix regulates the outcome of Smad-dependent autocrine TGF-β1-activated signaling, and therefore persistence of the myofibroblast phenotype. Increased activity and proliferation of resident fibroblasts are central to wound healing and fibrosis in all tissues. The fibroblast is the most abundant cell type in normal connective tissues and plays a central role in the synthesis, degradation, and remodeling of the extracellular matrix, both in health and disease. Although fibroblastic cells are traditionally considered to have a relatively uniform morphology, they are endowed with multiple functional properties, and several cytoskeletal differentiation markers have been described, which suggest that a phenotypic heterogeneity, related to distinct biological functions, also exists (1Sappino A.P. Schürch W. Gabbiani G. Lab. Investig. 1990; 63: 144-161PubMed Google Scholar). Fibroblasts normally express only two actin isoforms (β and γ). Recent studies, however, have demonstrated that in areas of fibrosis a sub-group of fibroblasts exists, which expresses the smooth muscle isoform of α-actin (α-SMA) 3The abbreviations used are: α-SMA, smooth muscle isoform of α-actin; TGF-β1, transforming growth factor-β1; 4MU, 4-methylumbelliferone; HA, hyaluronan; HAS, HA synthase; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; siRNA, short interfering RNA; Q-PCR, quantitative PCR; ANOVA, analysis of variance; HABP, HA-binding protein; HSD, Honest Significant Difference. that is normally expressed constitutively only in smooth muscle cells. It is now clear that these cells represent a sub-population of specialized fibroblasts that have developed a contractile phenotype that is expressed in a number of pathological settings associated with wound healing and fibrosis (2Gabbiani G. J. Pathol. 2003; 200: 500-503Crossref PubMed Scopus (1252) Google Scholar). These myofibroblasts are responsible for closure of wounds and for the formation of the collagen-rich scar. In addition, their presence in tissues has been established as a marker of progressive fibrosis (3Desmouliere A. Gabbiani G. Clark R.A.F. The Molecular and Cellular Biology of Wound Repair. 2nd Ed. Plenum Publishing Corp., New York1996: 391-423Google Scholar, 4Essawy M. Soylemezoglu O. Muchaneta-Kubara E.C. Shortland J. Brown C.B. El Nahas A.M. Nephrol. Dial. Transplant. 1997; 12: 43-50Crossref PubMed Scopus (177) Google Scholar, 5Goumenos D.S. Brown C.B. Shortland J. El Nahas A.M. Nephrol. Dial. Transplant. 1994; 9: 1418-1425PubMed Google Scholar, 6Tomasek J.J. Gabbiani G. Hinz B. Chaponnier C. Brown R.A. Nat. Rev. Mol. Cell Biol. 2002; 3: 349-363Crossref PubMed Scopus (3142) Google Scholar). The cytokine transforming growth factor-β (TGF-β) is recognized as a mediator of wound healing, and its aberrant expression has also been widely implicated in progressive tissue fibrosis (7Desmouliere A. Darby I.A. Gabbiani G. Lab. Investig. 2003; 83: 1689-1707Crossref PubMed Scopus (299) Google Scholar, 8Eddy A.A. Adv. Chronic Kidney Dis. 2005; 12: 353-365Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 9Schuppan D. Koda M. Bauer M. Hahn E.G. Acta Gastroenterol. Belg. 2000; 63: 366-370PubMed Google Scholar). In addition to its direct effect on extracellular matrix turnover, in vitro and in vivo evidence suggest that it is the primary driving force in fibroblast-myofibroblast differentiation (10Desmouliere A. Geinoz A. Gabbiani F. Gabbiani G. J. Cell Biol. 1993; 122: 103-111Crossref PubMed Scopus (1878) Google Scholar, 11Evans R.A. Tian Y.C. Steadman R. Phillips A.O. Exp. Cell Res. 2003; 282: 90-100Crossref PubMed Scopus (326) Google Scholar). Our previous work has demonstrated that TGF-β1-induced myofibroblast results in the induction of a stable phenotype that is persistent even following removal of exogenous TGF-β1 (11Evans R.A. Tian Y.C. Steadman R. Phillips A.O. Exp. Cell Res. 2003; 282: 90-100Crossref PubMed Scopus (326) Google Scholar). The mechanism by which stability of myofibroblast phenotype is maintained is, however, poorly understood. Hyaluronan (HA) is a ubiquitous connective tissue glycos-aminoglycan synthesized by HA synthase (HAS) enzymes of which three vertebrate genes have been isolated and characterized as follows: HAS1, HAS2, and HAS3 (12Spicer A.P. Kaback L.A. Smith T.J. Seldin M.F. J. Biol. Chem. 1998; 271: 25117-25124Abstract Full Text Full Text PDF Scopus (131) Google Scholar, 13Spicer A.P. McDonald J.A. J. Biol. Chem. 1998; 272: 1923-1932Abstract Full Text Full Text PDF Scopus (290) Google Scholar). It has a role in maintaining matrix stability and tissue hydration. It is known to play a major role in regulating cell-cell adhesion (14Kosaki R. Watanabe K. Yamaguchi Y. Cancer Res. 1999; 59: Google F. Y. O. M. K. A. 2002; PubMed Scopus Google Scholar, Phillips Phillips A.O. Kidney Full Text Full Text PDF PubMed Scopus Google Scholar, M. Nat. Cell Biol. 2002; PubMed Scopus Google differentiation A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google and proliferation M. J. PubMed Scopus Google Scholar, Biol. 1999; PubMed Scopus Google and it therefore plays an role in wound healing. In addition, it is in to in cells have demonstrated that HA TGF-β following with its Phillips A.O. J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have demonstrated that phenotypic of fibroblasts to myofibroblasts is associated with major in the and of HA Steadman R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). they have been to of and extracellular HA and to HA pericellular of HA synthesis in of phenotypic a role in fibroblast-myofibroblast D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar). fibroblast HA the of activation of TGF-β1-dependent J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These suggest that HA is a of fibroblast cell its role in the maintenance of myofibroblast phenotype has been The of the work in study is to the that maintain the stability of the myofibroblast phenotype. In the work on the importance of HA and its with TGF-β1 in were and and were and Cell of fibroblasts for were in a of and with were maintained in a and growth was to the cells The cells were in for h in differentiation was by addition of TGF-β1 (10 ng/ml) for 72 h in a myofibroblasts were with were in were cells In all fibroblasts were used as a were to in The was and the cells with phosphate-buffered the cells were in for were with for h to a further with the were with and in for h a further were with in for h were and by was used to TGF-β1, HAS2, and expression in The cells were to in and with to with and RNA to the was the of RNA was to of of and of The was to for by for of inhibitor and of were to and The was for for and for on a a was with the RNA the was in a of of of and and of and of was a of for and for for a was with the was for RNA and and as a The was used for of The is in the of the for the was the to the The for were The expression of the in to expression in was the following is the for the and is the for the Western blot analysis was used to expression of Smad2 and were to in and with were inhibitor and in The were and for The was and were by and the were of were with of and for was for and the were to a The was with Tris-buffered for h and with the primary antibody in Cell The were with and with the antibody for h in were to the TGF-β1 were to in and the TGF-β1 in the cell was a enzyme-linked to the TGF-β1 in the was and the with and activity was by as Phillips A.O. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The was a for Cancer of the cells were a and to were in for h and with of the Smad the a of of to of in and was by with a h was cells were with PBS, and were and myofibroblasts were to the cells for a further h. of the cells in in activity activity was the as in the activity was to of HA by of was used to the HA pericellular were in and for The was in an of of was to cells and for even The were for to the to the cells. cells were with in for to the addition of the were the cells with HA pericellular This was the as an of of were on a of the of the the areas of the cell was the of the was the of the cell the of HA were to in and the HA in the cell was a enzyme-linked HA-binding quantitative The used with a HA-binding to HA and an of to and HA in the and HA were in of the HA in the to the The were and with was to the with a a was to a was to the and the of the was in a HA were by the of the a the and HA and ng/ml) in the The is to with no with glycos-aminoglycan of Fibroblasts and and myofibroblasts were to in was and the cells were with with of growth no of fibroblasts and myofibroblasts with was in with the of was in of growth and to for were in growth to a of in a of The and the were and for a further The were to the in the of the that the was The was to of the and with for h. the was and with growth with no This was with for a further h to The of HAS2 by the was by to were for with only with multiple was used to by Honest Significant to The for multiple and an for The results are expressed as the data were and was considered of Fibroblasts in a of fibroblasts was as (11Evans R.A. Tian Y.C. Steadman R. Phillips A.O. Exp. Cell Res. 2003; 282: 90-100Crossref PubMed Scopus (326) Google Scholar, Steadman R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar). fibroblasts were by the addition of TGF-β1 (10 to a phenotype was by of demonstrated induction of was 72 h. the stability of phenotype was in model following removal of TGF-β1 cell and addition of for a further 120 h and of by demonstrated stability of phenotype was demonstrated by expression of following removal of TGF-β1 as with the expression of in an fibroblast data were also by analysis of α-SMA. was no expression in fibroblasts and for in myofibroblast was the of removal of TGF-β1 and for up to 120 h following its removal of with Smad and TGF-β1 the importance of TGF-β1 in the phenotypic of activation of Smad and the of TGF-β1 by Fibroblasts were for 72 h to phenotypic TGF-β1 was and was for a further 72 h. In the persistent activation of the TGF-β1 was as phosphorylation of was all following removal of TGF-β1. In no phosphorylation of was in fibroblasts of the was also associated with a in the expression of as by Western blot phenotypic TGF-β1 the of exogenous was the of both and synthesis all expression of TGF-β1 was that in an fibroblast The induction of TGF-β1 was also by a in the of TGF-β1 in the cell of myofibroblasts as with fibroblasts TGF-β1 is in a activation of which associated with of the Y. M. M. A. J. Cell Biol. 1993; PubMed Scopus Google Scholar, 2000; Google also of the by J. C. D. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The activity of the TGF-β1 by myofibroblasts was in a Phillips A.O. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). myofibroblasts was to cells with a was in activity following addition of myofibroblast as with fibroblast the presence of increased of TGF-β1 In was no in the of expression of the TGF-β receptor as by Western analysis The role of TGF-β1 activity in myofibroblast maintenance of phosphorylation of Smad was by Western blot analysis of phosphorylation of Smad2 following the addition of the TGF-β and TGF-β1 was inhibited by addition of (10 the removal of TGF-β1 following The on Smad were for 120 h. In to the no phosphorylation of Smad2 was in the thus that Smad activation was the of autocrine TGF-β1 the role of autocrine TGF-β1 in the maintenance of myofibroblast phenotype was by of by and by following inhibition of TGF-β1 the The results demonstrated that inhibition of TGF-β activity was associated with of these data suggest that induction of autocrine TGF-β1 synthesis in the myofibroblast to activation of and maintenance of the phenotype of the of TGF-β1 HA and previous have demonstrated that the of the fibroblast to the of TGF-β to myofibroblasts is related to the of the cell to HA a pericellular coat Steadman R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The hyaladherin is a in the regulation of HA matrix C. D. A. K. 2003; PubMed Scopus Google Scholar). expression in fibroblasts and myofibroblasts was and by all following phenotypic expression was in the myofibroblasts The autocrine TGF-β1 activity and was by the effect of inhibition of the on expression and the of an HA coat inhibition of TGF-β signaling, expression was to the in the fibroblast HA the of In are the cell of the fibroblasts by the and of pericellular HA This is as a of the cells. of the coat the of cells of phenotype a for the fibroblast coat of with the myofibroblast coat of of TGF-β1 by formation of the HA by the coat of with that of the myofibroblast of HA addition to HA demonstrated that fibroblast to myofibroblast phenotypic was on increased HA HA was in the fibroblasts and a of growth and addition of HA in the was by ELISA, the results of which demonstrated HA in the the myofibroblasts with the fibroblasts The role of increased HA in maintaining myofibroblast phenotype was by HA synthesis by the addition of to deplete the cytoplasmic pool of UDP-glucuronic acid, essential for HA chain as D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was to myofibroblasts the removal of TGF-β1 following and the of inhibition of HA synthesis were for up to 120 h. with previous fibroblast a HA pericellular coat following 72 h in and myofibroblasts a coat that is maintained in the of exogenous TGF-β1 In following inhibition of HA synthesis, myofibroblasts to an HA pericellular coat of the coat the of cells of phenotype a for the fibroblast coat of with the myofibroblast coat of of HA synthesis by formation of the HA by the coat of with that of the myofibroblast inhibition of HA synthesis and coat by the addition of in in expression of by HA and TGF-β effect of HA synthesis on autocrine TGF-β1-dependent activation of Smad was following addition of and Western analysis of Smad phosphorylation. with autocrine activation of Smad signaling, phosphorylation of both Smad2 and was demonstrated in myofibroblasts in the of exogenous TGF-β1. the previous results of expression of the myofibroblast marker following inhibition of HA synthesis, autocrine phosphorylation of Smad2 The role of HA was further by inhibition of HA synthesis by HAS2 was used to of HAS2 which was in cells of HAS2 was associated with a of TGF-β1 to in the fibroblasts as with inhibition of HA synthesis TGF-β1-dependent phosphorylation of the and The regulation of phenotype and differentiation tissue is an of the outcome of wound healing and the of In fibrosis, it has been established that the presence of myofibroblasts with of extracellular matrix and (2Gabbiani G. J. Pathol. 2003; 200: 500-503Crossref PubMed Scopus (1252) Google Scholar, 6Tomasek J.J. Gabbiani G. Hinz B. Chaponnier C. Brown R.A. Nat. Rev. Mol. Cell Biol. 2002; 3: 349-363Crossref PubMed Scopus (3142) Google Scholar, A. Darby I.A. Gabbiani G. Lab. Investig. 2003; 83: 1689-1707Crossref PubMed Scopus (299) Google Scholar). In these myofibroblasts activation and differentiation of a in which TGF-β1 has been implicated (10Desmouliere A. Geinoz A. Gabbiani F. Gabbiani G. J. Cell Biol. 1993; 122: 103-111Crossref PubMed Scopus (1878) Google Scholar, J.J. Exp. Cell Res. 2000; PubMed Scopus Google Scholar). of the is associated with the removal of myofibroblasts by a mechanism that A. M. Darby I.A. Gabbiani G. J. Pathol. Google Scholar). The persistence of myofibroblasts of tissue is a in J.J. Gabbiani G. Hinz B. Chaponnier C. Brown R.A. Nat. Rev. Mol. Cell Biol. 2002; 3: 349-363Crossref PubMed Scopus (3142) Google Scholar, J. Pathol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C. McDonald J.A. J. Pathol. Google Scholar, M. J. Pathol. Google Scholar). Myofibroblasts in tissues an phenotype. have demonstrated that following of wounds associated with the of in TGF-β1 receptor which to a persistent that results in of matrix and fibrosis G. C. J. Pathol. 1998; Google Scholar). Our data also TGF-β1 in the maintenance of the myofibroblast phenotype. The myofibroblast phenotype in was associated with of TGF-β1 in its and activation of the Smad inhibition of TGF-β in inhibition of Smad phosphorylation and also a of the myofibroblast phenotype as by expression of the myofibroblast marker α-SMA. This that persistence of the myofibroblast phenotype is because of of TGF-β1, which to activation of Smad in the of exogenous TGF-β1. This role of TGF-β1 in maintaining the persistence of the myofibroblast phenotype and Smad is with previous studies, which suggest that of the healing of wounds and closure of these wounds A. M. A. A. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google of wound healing, tissue are in these J.J. Wound 2000; PubMed Google Scholar). These of wound healing are with a to organ fibrosis, as are to fibrosis, fibrosis, fibrosis, as as fibrosis induced by induction of type with J. Exp. Pathol. PubMed Scopus Google Scholar). have demonstrated that fibroblasts with of HA are to increased of HA TGF-β1 that phenotypic D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar). Our now that the persistence of the myofibroblast phenotype is also associated with increased of inhibition of HA synthesis in the myofibroblast to a of both the pericellular HA coat and also of the myofibroblast as the inhibitor of HA synthesis to a of autocrine TGF-β1-dependent The importance of HA synthesis was further by inhibition of TGF-β1-dependent phenotypic activation by inhibition of HAS2 expression HA is a ubiquitous of extracellular matrix known for its role in maintaining matrix stability and tissue hydration. In addition, it has a major role in regulating cell through with and and also by of HA in with HA-binding Biol. 1999; PubMed Scopus Google Scholar, C.B. W. 1993; PubMed Scopus Google Scholar, W. C.B. Exp. Cell Res. PubMed Scopus Google Scholar, R. D. A. PubMed Scopus Google Scholar, W. C. Phillips A.O. J. Nephrol. PubMed Scopus Google Scholar). a it is an of tissue and has been implicated in a number of biological and pathological wound healing, and Cancer Res. 2000; Google Scholar, J.J. J. 1997; PubMed Scopus Google Scholar, G. Wound 1999; PubMed Scopus Google Scholar). In addition to the importance of the matrix HA in phenotypic activation of fibroblasts D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google have that of the myofibroblast phenotype is associated with the of a HA pericellular coat Steadman R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar). in study have demonstrated that inhibition of autocrine TGF-β1 and of the myofibroblast phenotype was associated with of the expression of the hyaladherin which has been demonstrated in cell to a of HA coat C. D. A. K. 2003; PubMed Scopus Google Scholar, W. C. Phillips A.O. J. Nephrol. PubMed Scopus Google Scholar). This of expression was associated with a of myofibroblast pericellular This that the presence of pericellular HA is in regulation of the to autocrine TGF-β1. This is with previous suggesting that the biological of HA only by the context in which it is also on the in which it is and pericellular Phillips Phillips A.O. Kidney Full Text Full Text PDF PubMed Scopus Google Scholar, W. C. Phillips A.O. J. Nephrol. PubMed Scopus Google Scholar, B. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Phillips A.O. Kidney Full Text Full Text PDF PubMed Scopus Google Scholar). Our previous in cells have demonstrated that HA TGF-β1 by altering the of TGF-β the cell in in the of activation and phosphorylation of the Smad2 and -3 Phillips A.O. J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In study inhibition of HA synthesis with by inhibition of HAS2 expression autocrine Smad phosphorylation, suggesting an mechanism by which HA autocrine TGF-β1 in cell in the are in that they without formation in of tissue and of Our previous work has demonstrated that fibroblasts the in their to in to TGF-β1 in that fibroblasts activation following TGF-β1 in is related to a of HA in the fibroblasts as with fibroblasts D. J. Phillips A. Steadman R. J. Biol. Chem. 282: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of HA were associated with the regulation of fibroblast to TGF-β J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). fibroblasts with TGF-β1 TGF-β1 an in of HA synthesis by the addition of in of HA in fibroblasts that in an to to the in This that TGF-β1 regulates the proliferation of fibroblasts with and in a It is, however, the of HA and the to a pericellular HA coat by the fibroblast that the outcome of J. Steadman R. Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The data in study a mechanism by which the of a pericellular HA coat in myofibroblasts Smad-dependent that maintain the myofibroblast the pericellular HA coat the of the cells to autocrine and of the HA pericellular matrix have been demonstrated to on C.B. W. 1993; PubMed Scopus Google Scholar). In addition to its role in the of pericellular HA, also in the activation of a number of and Phillips A.O. J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, F. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). The of a pericellular HA coat and of the phenotype is associated with of a to a and A. We therefore that the of the to autocrine Smad activation related to the of in with the Smad the of with TGF-β type and type Phillips A.O. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google of autocrine In the data that the persistence of the phenotype is on autocrine TGF-β1 the of a pericellular HA coat is an of the of the cells to autocrine TGF-β1. The data therefore further evidence to the that HA and its an matrix are to that fibroblast which are in the of wound healing, and organ
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