Release of Mechanical Tension Triggers Apoptosis of Human Fibroblasts in a Model of Regressing Granulation Tissue

Grinnell, Frederick; Zhu, Meifang; Carlson, Mark A.; Abrams, John

doi:10.1006/excr.1999.4440

Cited by 264 publications

(203 citation statements)

References 34 publications

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“…Grinnell et al reported that, in vitro, decreased stiffness of the extracellular matrix due to collagen relaxation inhibited myofibroblasts. 26 A similar mechanism could occur in vivo, with decreased extracellular matrix tension induced by the degradation of type III collagen by MMP14. Although the outcome of the myofibroblasts (that is, apoptosis or undifferentiation to a less active state) was unclear, remodeling of the extracellular matrix might have reduced internal stiffness resulting in a decrease of myofibroblasts.…”

Section: Discussionmentioning

confidence: 91%

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Fournié

Massoudi

et al. 2010

Gene Ther

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Once a corneal scar develops, surgical management remains the only option for visual rehabilitation. Corneal transplantation is the definitive treatment for a corneal scar. In addition to the challenges posed by graft rejections and other postoperative complications, the lack of high-quality donor corneas can limit the benefits possible with keratoplasty. The purpose of our study was to evaluate a new therapeutic strategy for treating corneal scarring by targeting collagen deposition. We overexpressed a fibril collagenase (matrix metalloproteinase 14 (MMP14)) to prevent collagen deposition in the scar tissue. We demonstrated that a single and simple direct injection of recombinant adeno-associated virus-based vector expressing murine MMP14 can modulate gene expression of murine stromal keratocytes. This tool opens new possibilities with regard to treatment. In a mouse model of corneal full-thickness incision, we observed that MMP14 overexpression reduced corneal opacity and expression of the major genes involved in corneal scarring, especially type III collagen and a-smooth muscle actin. These results represent proof of concept that gene transfer of MMP14 can reduce scar formation, which could have therapeutic applications after corneal trauma.

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Section: Discussionmentioning

confidence: 91%

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Fournié

Massoudi

et al. 2010

Gene Ther

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“…The contractility of whole cell populations was quantified with the use of stress-released collagen lattices (Mochitate et al, 1991;Tomasek et al, 1992;Grinnell et al, 1999b). Our results indicate a correlation between the level of ␣-SMA expression and fibroblast contraction.…”

mentioning

confidence: 80%

Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity

Hinz

Celetta

Tomasek³

et al. 2001

MBoC

1,135

947

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To evaluate whether ␣-smooth muscle actin (␣-SMA) plays a role in fibroblast contractility, we first compared the contractile activity of rat subcutaneous fibroblasts (SCFs), expressing low levels of ␣-SMA, with that of lung fibroblasts (LFs), expressing high levels of ␣-SMA, with the use of silicone substrates of different stiffness degrees. On medium stiffness substrates the percentage of cells producing wrinkles was similar to that of ␣-SMA-positive cells in each fibroblast population. On high stiffness substrates, wrinkle production was limited to a subpopulation of LFs very positive for ␣-SMA. In a second approach, we measured the isotonic contraction of SCF-and LF-populated attached collagen lattices. SCFs exhibited 41% diameter reduction compared with 63% by LFs. TGF␤1 increased ␣-SMA expression and lattice contraction by SCFs to the levels of LFs; TGF␤-antagonizing agents reduced ␣-SMA expression and lattice contraction by LFs to the level of SCFs. Finally, 3T3 fibroblasts transiently or permanently transfected with ␣-SMA cDNA exhibited a significantly higher lattice contraction compared with wild-type 3T3 fibroblasts or to fibroblasts transfected with ␣-cardiac and ␤-or ␥-cytoplasmic actin. This took place in the absence of any change in smooth muscle or nonmuscle myosin heavy-chain expression. Our results indicate that an increased ␣-SMA expression is sufficient to enhance fibroblast contractile activity. INTRODUCTIONEarly during healing of an open wound, resident dermal fibroblasts proliferate from the wound margin and migrate into the provisional matrix composed of a fibrin clot. About 1 week after wounding, the provisional matrix is replaced by neo-formed connective tissue, known as granulation tissue, essentially composed of small vessels, extracellular matrix, and fibroblastic cells that become activated and modulate into myofibroblasts. The main feature of myofibroblasts is represented by an important contractile apparatus similar to that of smooth muscle (Gabbiani et al., 1971), and in particular by the neo-expression of ␣-smooth muscle actin (␣-SMA), the actin isoform typical of vascular smooth muscle cells (Skalli et al., 1986). Myofibroblasts are recognized to play a central role in closing the wound tissue, through their capacity to produce a strong contractile force (for review see Grinnell, 1994;Rønnov-Jessen et al., 1996;Powell et al., 1999;Serini and Gabbiani, 1999), possibly generated within stress fibers, similar to those present in cultured fibroblasts (Skalli et al., 1986;Serini and Gabbiani, 1999). Because wound contraction takes place when de novo expressed ␣-SMA is incorporated in stress fibers (Darby et al., 1990), it has been suggested that this actin isoform plays an important role in granulation tissue contraction (for review see Serini and Gabbiani, 1999). Although stress fibers have been proposed to function as contractile organelles (Burridge, 1981;Katoh et al., 1998) and their presence has been correlated with the production of isometric tension (Harris et al., 1981), at p...

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“…Although the precise mechanism(s) of myofibroblast apoptosis in the resolution of wound healing and tissue repair are not well defined, anoikis is likely a relevant model to study apoptotic mechanisms since cell adhesion and biomechanical tension unloading appear to play important roles in this physiological context [44,45]. Our observations that the PI3K-AKT and integrin-FAK pathways are activated in a combinatorial manner by TGF-β1 to promote myofibroblast survival have important implications for broader understanding of dysregulated tissue repair and fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

224

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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Release of Mechanical Tension Triggers Apoptosis of Human Fibroblasts in a Model of Regressing Granulation Tissue

Cited by 264 publications

References 34 publications

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

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