Integrins as Modulators of Transforming Growth Factor Beta Signaling in Dermal Fibroblasts During Skin Regeneration After Injury

Transforming growth factor-beta, a potent modulator of cell function, induces fibroblasts cultured on plastic to increase collagen synthesis. In 5- and 7-day porcine skin wounds, which have minimal to moderate collagen matrix, respectively, transforming growth factor-beta and type I procollagen were coordinately expressed throughout the granulation tissue. However, in 10-day collagen-rich granulation tissue type I procollagen expression diminished despite persistence of transforming growth factor-beta. To investigate whether collagen matrix attenuates the collagen-synthetic response of fibroblasts to transforming growth factor-beta, we cultured human dermal fibroblasts in conditions that simulate collagen-rich granulation tissue. Therefore, human dermal fibroblasts were suspended in attached collagen gels and collagen and noncollagen production was assayed in the absence and presence of transforming growth factor-beta. Although transforming growth factor-beta stimulated collagen synthesis by fibroblasts cultured in the collagen gels, these fibroblasts consistently produced less collagen than similarly treated fibroblasts cultured on plastic. This phenomenon was not secondary to nonspecific binding of transforming growth factor-beta to the collagen matrix. Fibroblasts cultured in a fibrin gel responded to transforming growth factor-beta similarly to fibroblasts cultured on plastic. Using immunofluorescence probes to type I procollagen, we observed that transforming growth factor-beta increased type I procollagen expression in most fibroblasts cultured on plastic, but only in occasional fibroblasts cultured in collagen gels. From these data we conclude that collagen matrices attenuate the collagen synthetic response of fibroblast to transforming growth factor-beta in vitro and possibly in vivo.

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Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta.

Journal of Experimental Medicine ◽

10.1084/jem.165.1.251 ◽

1987 ◽

Vol 165 (1) ◽

pp. 251-256 ◽

Cited By ~ 522

Author(s):

A E Postlethwaite ◽

J Keski-Oja ◽

H L Moses ◽

A H Kang

Keyword(s):

Growth Factor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Human Fibroblasts ◽

Critical Role ◽

Dermal Fibroblasts ◽

Type I ◽

Tgf Beta ◽

Chemotactic Migration ◽

Growth Factor Beta

Transforming growth factor beta (TGF-beta) is a potent chemoattractant in vitro for human dermal fibroblasts. Intact disulfide and perhaps the dimeric structure of TGF-beta is essential for its ability to stimulate chemotactic migration of fibroblasts, since reduction with 2-ME results in a marked loss of its potency as a chemoattractant. Although epidermal growth factor (EGF) appears to be capable of modulating some effects of TGF-beta, it does not alter the chemotactic response of fibroblasts to TGF-beta. Specific polyvalent rabbit antibodies to homogeneously pure TGF-beta block its chemotactic activity but has no effect on the other chemoattractants tested (platelet-derived growth factor, fibronectin, and denatured type I collagen). Since TGF-beta is secreted by a variety of neoplastic and normal cells including platelets, monocytes/macrophages, and lymphocytes, it may play a critical role in vivo in embryogenesis, host response to tumors, and the repair response that follows damage to tissues by immune and nonimmune reactions.

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Faculty Opinions recommendation of Matrix contraction by dermal fibroblasts requires transforming growth factor-beta/activin-linked kinase 5, heparan sulfate-containing proteoglycans, and MEK/ERK: insights into pathological scarring in chronic fibrotic disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1029551.347425 ◽

2005 ◽

Author(s):

Giulio Gabbiani

Keyword(s):

Growth Factor ◽

Heparan Sulfate ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Dermal Fibroblasts ◽

Fibrotic Disease ◽

Growth Factor Beta ◽

Matrix Contraction

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Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts

PLoS ONE ◽

10.1371/journal.pone.0218178 ◽

2019 ◽

Vol 14 (6) ◽

pp. e0218178 ◽

Cited By ~ 7

Author(s):

Alexander Peidl ◽

Bernard Perbal ◽

Andrew Leask

Keyword(s):

Growth Factor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Family Members ◽

Dermal Fibroblasts ◽

Human Dermal Fibroblasts ◽

Ccn Family ◽

Yin Yang ◽

Growth Factor Beta ◽

Ccn3 Expression

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Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213031 ◽

2018 ◽

Vol 77 (9) ◽

pp. 1362-1371 ◽

Cited By ~ 36

Author(s):

Christopher P Denton ◽

Voon H Ong ◽

Shiwen Xu ◽

Haiyin Chen-Harris ◽

Zora Modrusan ◽

...

Keyword(s):

Systemic Sclerosis ◽

Growth Factor ◽

Transforming Growth Factor Beta ◽

Interleukin 6 ◽

Transforming Growth Factor ◽

Expression Profiles ◽

Dermal Fibroblasts ◽

Sequencing Analysis ◽

Growth Factor Beta

ObjectivesSkin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.MethodsWe analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.ResultsThe hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.ConclusionsWe demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.Trial registration numberNCT01532869; Post-results.

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