Modulation of Collagen Synthesis by Transforming Growth Factor-β in Keloid and Hypertrophic Scar Fibroblasts

Younai, Soheil; Nichter, Larry S.; Wellisz, Tadeusz; Reinisch, John F.; Nimni, Marcel E.; Tuan, Tai‐Lan

doi:10.1097/00000637-199408000-00005

Cited by 185 publications

(124 citation statements)

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“…In addition to its role in blood coagulation, fibrin has been suggested to play a role in the wound-healing process itself. Fibrin was studied in vitro in relation to the migration and proliferation of fibroblasts and to the absorption of proteins such as fibronectin (Younai et al 1994(Younai et al , 1996. Those studies not only showed that fibrin works as a biological glue that connects tissues and stops bleeding, but also supported the notion that fi brin promotes a migratio n / proliferation of endothelium and fibroblasts and a remodeling of the extracellular matrix.…”

Section: Discussionmentioning

confidence: 91%

Fibrin Stimulates the Proliferation of Human Keratinocytes through the Autocrine Mechanism of Transforming Growth Factor-.ALPHA. and Epidermal Growth Factor Receptor

Yamamoto

Yanaga²,

Nishina³

et al. 2005

Tohoku J. Exp. Med.

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In the field of dermatology and plastic and reconstructive surgery, fibrin gel is regarded as a material that promotes wound healing. To test the hypothesis that fibrin may promote the growth of the epidermis, we examined its effects on the proliferation of cultured keratinocytes. Human keratinocytes were cultivated in fibrincoated wells, and the cell numbers and transforming growth factor (TGF)-α , secreted into the cultured medium, were measured. We also assessed the capacity of epidermal growth factor receptor (EGF-R) that is responsible for all known actions of TGF-α and epidermal growth factor. The keratinocytes increased dramatically in their number, and the TGF-α secretion and the binding capacity of EGF-R were also increased dramatically in the presence of fibrin. These findings suggest that fibrin supports the proliferation of keratinocytes in an autocrine fashion via EGF-R; namely, fibrin stimulates keratinocytes to secrete TGF-α, which in turn increases cell proliferation and EGF-R capacity. We propose that fibrin can support the wound healing process of the epidermis via the TGF-α /EGF-R pathway.fibrin; keratinocytes; TGF-α ; EGF-R; wound healing © 2005 Tohoku University Medical PressFibrin gel is commonly used in clinical applications, as it had been originally developed as a biological glue for wound closure and tissue fixation. Therefore, it has mainly been used to stop bleeding and the loss of bodily fluid. Recently in the fields of dermatology and plastic and reconstructive surgery, fibrin gel began to be regarded as a material that promotes the wound-healing process and results in a good take rate for epidermis grafts and in faster wound healing.There are several clinical reports on the use of fibrin gel as a wound healing promoter. Ronfard

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Section: Discussionmentioning

confidence: 91%

Fibrin Stimulates the Proliferation of Human Keratinocytes through the Autocrine Mechanism of Transforming Growth Factor-.ALPHA. and Epidermal Growth Factor Receptor

Yamamoto

Yanaga²,

Nishina³

et al. 2005

Tohoku J. Exp. Med.

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“…Previous studies showed that cultured fibroblasts often exhibit characteristics typical of their in vivo phenotypes (Calderon et al, 1996;Tuan and Nichter, 1998;Yoshimoto et al, 1999;Younai et al, 1994). Although we described higher levels of caspase-2 and -3 expression in hypertrophic scars and keloid, Wassermann et al (1998) reported that the immunostaining levels of ICE and Fas were decreased in hypertrophic scar-derived fibroblasts.…”

Section: Akasaka Et Almentioning

confidence: 99%

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

Akasaka

Ishikawa

Ono

et al. 2000

Laboratory Investigation

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SUMMARY:Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and development of pathological scarring. To examine the phenomenon of apoptosis and its involvement in the process of pathological scarring, we immunohistochemically quantified differential levels of expression of caspase-3 and -2, which are activated during apoptosis in vitro, in surgical resected scar tissues. We divided 33 cases of normally healed flat scars and 18 cases of pathological scars (15 cases of hypertrophic scars and 3 cases of keloid) into three groups (S1 ϭ Ͻ10 months' duration; S2 ϭ 10 to 40 months' duration; and S3 ϭ Ͼ40 months' duration) according to the duration of scar. In all three groups examined, the semiquantitative scores for caspase-3 staining were significantly higher for the combination of hypertrophic scars and keloid as a group compared with normally healed flat scars, suggesting reduced cell survival and increased apoptotic cell death in hypertrophic scars and keloid. Apoptosis and caspase proteolytic activities were examined in vitro using two flat scar-derived fibroblast lines (FSFB-1 and -2) and two keloid-derived fibroblast lines (KFB-1 and -2). After 24 hours of serum deprivation, apoptotic cells were significantly increased in both KFB lines, whereas serum deprivation of FSFB-1 cells did not result in a significant increase in apoptotic cell number. After serum deprivation, significant increases in caspase-3 proteolytic activities were detected in both KFB lines compared with both FSFB lines. In contrast, no significant differences with caspase-8 activity were observed between similarly treated KFB and FSFB lines. Furthermore, serum deprivation-induced apoptosis of KFB-2 cells was significantly inhibited by the caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD-FMK), indicating that caspase-3 is important for serum deprivation-induced apoptosis in KFB-2 cells. Considering the role of caspase-3 as a key effector molecule in the execution of apoptotic stimuli, our results suggested that enhanced expression of caspase-3 in hypertrophic scars and keloid induces apoptosis of fibroblasts, which may play a role in the process of pathological scarring. (Lab Invest 2000, 80:345-357).

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“…At the cellular level, increased levels of cytokines and growth factors, or their receptors, and sensitization of mitogenic response to these secreted factors after wounding in KFs have been suggested to play a role in keloid pathogenesis (Calderon et al, 1996). Transforming growth factor (TGF)-b1 and TGF-b2 were found to be elevated in KFs (Lee et al, 1999), and increased sensitivity to TGF-b1 in KFs increased fibronectin (Babu et al, 1992) and collagen production, and cell proliferation (Younai et al, 1994). Platelet-derived growth factor (PDGF)a receptor expression was shown to be enhanced in KFs, which corresponded to increased mitotic response upon exposure to all three PDGF isoforms (Haisa et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.

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Modulation of Collagen Synthesis by Transforming Growth Factor-β in Keloid and Hypertrophic Scar Fibroblasts

Cited by 185 publications

References 0 publications

Fibrin Stimulates the Proliferation of Human Keratinocytes through the Autocrine Mechanism of Transforming Growth Factor-.ALPHA. and Epidermal Growth Factor Receptor

Fibrin Stimulates the Proliferation of Human Keratinocytes through the Autocrine Mechanism of Transforming Growth Factor-.ALPHA. and Epidermal Growth Factor Receptor

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

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