Expression of α-smooth muscle actin (α-SMA) renders fibroblasts highly contractile and hallmarks myofibroblast differentiation. We identify α-SMA as a mechanosensitive protein that is recruited to stress fibers under high tension. Generation of this threshold tension requires the anchoring of stress fibers at sites of 8–30-μm-long “supermature” focal adhesions (suFAs), which exert a stress approximately fourfold higher (∼12 nN/μm2) on micropatterned deformable substrates than 2–6-μm-long classical FAs. Inhibition of suFA formation by growing myofibroblasts on substrates with a compliance of ≤11 kPa and on rigid micropatterns of 6-μm-long classical FA islets confines α-SMA to the cytosol. Reincorporation of α-SMA into stress fibers is established by stretching 6-μm-long classical FAs to 8.1-μm-long suFA islets on extendable membranes; the same stretch producing 5.4-μm-long classical FAs from initially 4-μm-long islets is without effect. We propose that the different molecular composition and higher phosphorylation of FAs on supermature islets, compared with FAs on classical islets, accounts for higher stress resistance.
Myofibroblasts of wound granulation tissue, in contrast to dermal fibroblasts, join stress fibers at sites of cadherin-type intercellular adherens junctions (AJs). However, the function of myofibroblast AJs, their molecular composition, and the mechanisms of their formation are largely unknown. We demonstrate that fibroblasts change cadherin expression from N-cadherin in early wounds to OB-cadherin in contractile wounds, populated with alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. A similar shift occurs during myofibroblast differentiation in culture and seems to be responsible for the homotypic segregation of alpha-SMA-positive and -negative fibroblasts in suspension. AJs of plated myofibroblasts are reinforced by alpha-SMA-mediated contractile activity, resulting in high mechanical resistance as demonstrated by subjecting cell pairs to hydrodynamic forces in a flow chamber. A peptide that inhibits alpha-SMA-mediated contractile force causes the reorganization of large stripe-like AJs to belt-like contacts as shown for enhanced green fluorescent protein-alpha-catenin-transfected cells and is associated with a reduced mechanical resistance. Anti-OB-cadherin but not anti-N-cadherin peptides reduce the contraction of myofibroblast-populated collagen gels, suggesting that AJs are instrumental for myofibroblast contractile activity.
depolymerization reduces single-bond strength to the level of cadherin constructs missing the cytoplasmic domain. Hence, fibroblasts reinforce intercellular contacts by: (1) switching from N-to OB-cadherin expression; (2) increasing the strength of single-molecule bonds in three distinct steps; and (3) actinpromoted intrinsic activation of cadherin extracellular binding. We propose that this plasticity adapts fibroblast adhesions to the changing mechanical microenvironment of tissue under remodeling. Supplementary material available online at
We show in this paper that 13-methyltetradecanoic acid (13-MTD) can be used as a structually labeled marker for investigating the mobility of fatty acyl chains in adipose tissue in the rat. The presence of an omega-1 methyl group allows easy quantitation by gas liquid chromatography (GLC) and permits an assessment to be made of any oxidation and chain elongation reactions with reincorporation of the label into the adipose tissue, since the iso-acyl chain is well resolved from odd or even-numbered homologous fatty acids with straight chains. The kinetics of uptake and loss of the structural label were different for adipose tissue taken from the various sites which were sampled, namely post abdominal, mesenteric, perirenal, pericardiac and subcutaneous adipose tissue as well as the epidydimal fat pads. We also report preliminary results in man which confirm that the method is applicable to human clinical studies and that 13-MTD kinetics differ for adipose tissue taken from the 3 different subcutaneous sites--waist, arm and thigh.
ICR-derived strain with gulomerulonephrisis (ICGN) mouse derived from ICR mouse is a newly established mouse strain with hereditary nephrotic syndrome. The affected ICGN mice consistently show the clinical signs of nephrotic syndrome, developing various degrees. The lesions consist of thickened capillary basement membrane, enlarged mesangium without cellular proliferation, and tubulointerstitial fibrosis. Based on these histopathological findings and clinical biochemical data, ICGN strain mouse is considered to be a good experimental model for human idiopathic nephrotic syndrome. Extracellular matrix (ECM) components provide structural integrity to the tissues, and mediate regulation of cell growth, migration, differentiation, etc. The damaged cells have increased secretion of ECM components. This is a kind of self-protecting reaction that is associated with healing process against injury. However, the hyperaccumulation of ECM components leads to fibrosis, a pathological phenomenon. Therefore, it is very important to make clearly the process of fibrosis in ICGN strain mouse. In this study, the expression and localization of transforming growth factor beta1 (TGF-b1), TGF-b1 type I receptor (TGFR1), and bone morphogenic protein (BMP)-7, which regulate the signals of TGF-b1 negatively, were investigated by using immunohistochemical staining and Western blotting. High expression levels of TGF-b1 and TGFR1 were observed in tubular epithelial cells of middle stage-ICGN mice as compared with those of control ICR mice. BMP-7 was strongly expressed in tubular epithelium of ICR mice, but it decreased with the progression of renal disease in ICGN mice. Moreover, no localization of BMP-7 in expanded tubular epithelial cells in ICGN mice was seen. These data suggest that the increase of TGF-b1 and TGFR1 and the degradation of negative regulation of TGF-b1 by BMP-7 in middle and late stages of ICGN mice play an important role in renal fibrosis of ICGN mice. The present findings may contribute to elucidate the pathogenic mechanisms of human idiopathic nephrotic syndrome.Common Achilles tendon ruptures are usually not fixed by absorbable sutures due to limitations in their strength properties. Modern technology has made it possible to develop bioabsorbable sutures with prolonged strength retention. To evaluate histologically tissue reactions and biodegradation of poly-L/D-lactide (PLDLA) sutures implanted in Achilles tendon of rabbits. Fifteen rabbits were operated on and killed within a time schedule of 2, 6 and 12 weeks, with five rabbits in per period. PLDLA monofilament sutures (Tampere University of Technology, Tampere, Finland) were implanted inside the rabbit medial gastrocnemius tendon for biocompatibility testing. Polyglyconate (4.0) monofilament sutures (Maxon Ò , Cyanamid of Great Britain Ltd., Gosport, UK) with the same diameter were implanted in the contralateral tendon. The histology was studied in hard-resin embedded samples and the thickness of the encapsule membrane was determined histomorphometrically.PLDLA hav...
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