Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat.

ffrench‐Constant, Charles; Water, Livingston Van De; Dvorak, Harold F.; Hynes, Richard O.

doi:10.1083/jcb.109.2.903

Cited by 446 publications

(231 citation statements)

References 68 publications

(86 reference statements)

Supporting

Mentioning

219

Contrasting

Order By: Relevance

“…The concept that alternative splicing of FN in general, and EDA cFN in particular, is essential in wound healing has been well established by our group and others (7,38,39). EDA cFN (also termed oncofetal or embryonic FN) is an important substrate for cell migration (40), adhesion (41), and myofibroblast differentiation (Reference 6 and data presented here).…”

Section: Discussionmentioning

confidence: 81%

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Muro¹,

Moretti²,

Moore³

et al. 2008

Am J Respir Crit Care Med

261

254

View full text Add to dashboard Cite

Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen. Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis. Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and a-smooth muscle actin (a-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes. Measurements and Main Results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and a-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wildtype controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer a-SMA-expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-b and decreased lung fibroblast responsiveness to active TGF-b in vitro. Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-b activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.Keywords: fibrosis; fibronectin; TGF-b; myofibroblast Fibroproliferative disorders, characterized by the increased production and deposition of extracellular matrix (ECM) proteins in tissues, are not well understood despite major efforts to elucidate pathogenic mechanisms. Recent attention has focused on ECM components and mesenchymal cell phenotypes as being critical to the development of fibrosis (1, 2). The ECM is a highly dynamic complex that varies in composition according to its tissue localization and physiologic circumstances. Collagens are the predominant ECM proteins identified in fibrotic lesions and are the hallmark of fibroproliferative diseases, but fibronectins (FNs) are also present in abnormally large quantities and localize to areas of active fibrogenesis (3, 4).FNs are multifunctional glycoproteins found in the ECM of tissues and plasma. Two main forms of FN exist: plasma FN, a dimeric and soluble form produced by hepatocytes that lacks the EDA and EDB sequences, and cellular FN (cFN), a multimeric form synthesized by mesenchymal, epithelial, and inflammatory cells, which is deposited in ECM fibrils and that contains variable proportions of the extra type III domains A and B (EDA and EDB) (5...

show abstract

Section: Discussionmentioning

confidence: 81%

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Muro¹,

Moretti²,

Moore³

et al. 2008

Am J Respir Crit Care Med

261

254

View full text Add to dashboard Cite

show abstract

“…The expression of ED-A FN in healing wounds (Ffrench-Constant et al, 1989;Brown et al, 1993) precedes the appearance of ␣-SMA-positive myofibroblasts and is essential to mediate TGF␤1-induced ␣-SMA expression (Serini et al, 1998). The mechanism of specific antibodies and of TGF␤-sR action on TGF␤ appears obvious (Komesli et al, 1998); however, the mechanism through which rED-A inhibits TGF␤-mediated ␣-SMA expression is at present unclear.…”

Section: Discussionmentioning

confidence: 99%

Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity

Hinz

Celetta

Tomasek³

et al. 2001

MBoC

1,114

947

View full text Add to dashboard Cite

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...

show abstract

“…For example, fibronectin, regulated by the actions of TGF-␤ (40), may play an important role in compensatory repair mechanisms of the tissue. Indeed, fibronectin has been found to be of major importance during wound healing (41,42). In particular, fibronectin mRNA is upregulated in regenerating tissue of damaged kidneys (43).…”

Section: Discussionmentioning

confidence: 99%

Renal mRNA Levels as Prognostic Tools in Kidney Diseases

Eikmans¹,

Baelde²,

Hagen

et al. 2003

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Molecular biologic techniques are currently considered as new diagnostic and prognostic parameters with a sensitivity and specificity exceeding those of histologic and functional data currently used in clinical practice. The results in various clinical settings have been of limited value up to now. This study is an investigation of the use of tissue levels of RNA determined in routine clinical kidney biopsies as prognostic tools. The focus was on RNA encoding for molecules known to be involved in the pathogenesis of renal disorders. Fresh kidney biopsy tissue was obtained from 52 patients with various renal diseases. The GFR was followed for 12 mo. The extent of glomerulosclerosis and interstitial fibrosis in the biopsies was determined with quantitative digital image analysis. Glomerular and tubulointerstitial compartments from each biopsy specimen were separated, and mRNA levels of TGF-␤, collagen I, collagen IV, and fibronectin were quantitated by real-time PCR. Correlations, along with 95% confidence intervals (CI), between all variables tested at time biopsy were determined. To assess their prognostic value, these variables were correlated with the slope of GFR within several time intervals after biopsy. In addition, to evaluate the predictive value of the variables for outcome in individual patients, differences for each variable were tested between patients showing progressive decline in renal function (slope GFR Ͻ 0) and patients showing stable or improving renal function over time (slope GFR Ն 0). In chronic renal diseases, the extent of histologic damage correlated with the GFR at the time of biopsy (r ϭ Ϫ0.44; CI Ϫ0.68 to Ϫ0.11), but it did not correlate with the slope expressing a change in GFR after the biopsy. Tubulointerstitial TGF-␤ mRNA levels correlated with the rate of change in GFR between time of biopsy and 1 mo later (r ϭ 0.41; CI, 0.07 to 0.67). The GFR at the time of biopsy correlated with the slope of change in GFR between time of biopsy and 12 mo later (r ϭ Ϫ0.50; CI, Ϫ0.73 to Ϫ0.18). In chronic renal diseases, glomerular fibronectin mRNA levels, in comparison with the GFR at time of biopsy, correlated relatively strongly with the slope of change in GFR between 3 and 12 mo (r ϭ 0.50; CI, 0.16 to 0.74). Patients with favorable renal outcome after 12 mo showed significantly higher TGF-␤ mRNA levels and lower proteinuria levels at time of biopsy (P Ͻ 0.05) than patients with a progressive decline in renal function. This study shows that mRNA levels measured in kidney biopsies can function as prognostic tools in human renal diseases. In particular, relatively high levels of tubulointerstitial TGF-␤ mRNA and glomerular fibronectin mRNA are associated with less deterioration in renal function.

show abstract

Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat.

Cited by 446 publications

References 68 publications

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity

Renal mRNA Levels as Prognostic Tools in Kidney Diseases

Contact Info

Product

Resources

About