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PubMed2001

Angiotensin II type 1 receptor regulation and differential trophic effects on rat cardiac myofibroblasts after acute myocardial infarction.

Fibroblast growth in the scar and surviving tissue is a key element of the remodeling post myocardial infarction. The regulation of fibroblast growth after acute myocardial infarction remains to be determined. Recently, Angiotensin II has been demonstrated to be a mitogen for neonatal cardiac fibroblasts. In this study adult rat cardiac fibroblasts were isolated from different regions of the infarcted rat heart and Angiotensin II effects examined. Adult Wistar-rats were sham operated or left coronary artery ligated. After 4 days, hearts were removed and fibroblasts from sham operated, infarct- and non-infarct regions of the left ventricle isolated. Radioligand binding studies were performed and cell number, cell area, total protein, and AT(1) receptor mRNA after stimulation determined. Radioligand binding studies demonstrated that myofibroblasts expressed a single class of high affinity Angiotensin II AT(1) receptors. Myofibroblasts from the infarct area revealed a lower maximal binding capacity, compared to sham operated myocardium. Conversely, myofibroblasts from the non-infarct area had a higher expression of Angiotensin II AT(1) receptor mRNA compared to sham operated myofibroblasts. Angiotensin II (1 microM, 48 h) increased cell-number in sham operated and non-infarct, but not in infarct myofibroblasts. Angiotensin II elevated total protein in sham operated, non-infarct, and infarct myofibroblasts. In addition, Angiotensin II increased cell area in sham operated and infarct myofibroblasts. These data demonstrate that Angiotensin II acted as a mitogen in sham operated and non-infarct myofibroblasts and stimulated hypertrophy in infarct myofibroblasts. These regional different effects of Angiotensin II might participate in the remodeling post myocardial infarction.

Angiotensin II↗
PubMed1996

Myofibroblasts in the healing lapine medial collateral ligament: possible mechanisms of contraction.

The specific objective of this study was to determine the chronology of the appearance of the myofibroblast in the healing ligament. The overall goal of our work is to elucidate the cellular mechanism of contraction in this tissue. The myofibroblast has been found to be responsible for wound contraction in many tissues and to be the cause of the contracture in several pathological conditions. This cell type contains the actin isoform previously thought to be unique to smooth muscle cells and displays certain characteristic features at the ultrastructural level. In 26 New Zealand White male rabbits, the right medial collateral ligament was transected, whereas the left medial collateral ligament received a sham operation. The central third of the ligament (ligament scar tissue) was evaluated at 2, 3, 6, 8, 10, and 12 weeks postoperatively by immunohistochemical techniques, transmission electron microscopy, and Western blot analyses. Three other rabbits served as anatomic controls. During the early reparative phase (2 and 3 weeks after transection), there was an increase in the number of cells containing alpha-smooth muscle actin as well as augmentation of the alpha-smooth muscle actin content within each cell--a finding attributed to smooth muscle cells and pericytes associated with neovascularity. No myofibroblasts were detected at this stage, immediately postoperatively, or in the sham-operation controls. Ligaments in the remodeling phase of healing (6, 8, 10, and 12 weeks) exhibited alpha-smooth muscle actin in fibroblasts (myofibroblasts) as well as in vascular pericytes and smooth muscle cells. During this stage of healing, transmission electron microscopy demonstrated an increase in the number of cells displaying myofibroblastic features. It was estimated that at 12 weeks of healing 10% of the cells at the site of injury were myofibroblasts. This is the first definitive finding of myofibroblasts in the injury site of the healing ligament, to our knowledge. The appearance of myofibroblasts in the 6-12 week healing period, the interval during which the ligament has been shown to contract in studies by other investigators, is a rationale for a hypothesis that a cellular contractile apparatus comprising alpha-smooth muscle actin (i.e., the myofibroblast) may contribute to the recovery of original ligament length (and normal in situ strain).

Actins↗
PubMed1984

The intermediate filament cytoskeleton of myofibroblasts: an immunofluorescence and ultrastructural study.

The intermediate filament cytoskeleton of stromal myofibroblasts from a series of twenty-eight infiltrating ductal breast carcinomas was examined by transmission electron microscopy (TEM) and indirect immunofluorescence (IF), the latter using antibodies to desmin, vimentin and prekeratin. Three cases of fibromatoses, selected as an additional source of myofibroblasts, were processed in the same manner. Stromal myofibroblasts from invasive ductal breast carcinomas rich in actin and readily identified by IF, were most numerous in the "young" edematous mesenchyme, areas corresponding to early stromal invasion or the peripheral invasive cellular front. Within the central sclerotic zone wherein clusters of neoplastic epithelial cells were surrounded by abundant collagen, most stromal cells corresponded by TEM to fibroblasts. In like fashion, myofibroblasts were most numerous in cellular, poorly collagenized portions of fibromatoses. By IF the only detectable intermediate filament protein of myofibroblasts in these two settings was vimentin. Since the appearance of stromal myofibroblasts appears to be associated with stromal invasion by malignant epithelium, their development by modulation of pre-existent periductal fibroblasts is postulated. With the exception of vascular smooth muscle cells and endothelial cells, the only periductal mesenchymal cells shown to contain vimentin were fibroblasts. The lack of desmin in myofibroblasts constitutes evidence against an origin from vascular smooth muscle cells. Because the molecular markers (intermediate filament proteins) of stromal cell differentiation presented quantitative but not qualitative modifications, the transformation of fibroblasts into myofibroblasts is quite likely, suggesting that myofibroblasts may be more closely related to fibroblasts than to smooth muscle cells.

Breast↗
PubMed2001

Pancreatic ductal myofibroblasts. Proliferative patterns in various pathologic situations.

Myofibroblasts in the periacinar area of the pancreas have been demonstrated to mediate fibrogenesis in pancreatic fibrosis. However, only a few reports have described myofibroblasts in the pancreatic duct. To elucidate the presence of myofibroblasts in the pancreatic ductal wall, we performed an immunohistochemical study, using immunostains for both alpha-smooth muscle actin (alphaSMA) and desmin, and an electron microscopic study on surgically resected pancreatic specimens from 10, 23, 23, and 56 cases of focal pancreatitis (FP), chronic pancreatitis (CP), pancreatic carcinoma (PCa), and carcinoma of the papilla of Vater (VPCa), respectively. All cases showed localized stenosis of the main pancreatic duct by means of preoperative pancreatography. As controls, 20 autopsy cases were studied. alphaSMA-positive and desmin-negative cells existed in the ductal walls of controls and were revealed as myofibroblasts by means of electron microscopy. In six FPs, proliferation of myofibroblasts was observed at the stenotic portion. In VPCas, myofibroblasts mainly proliferated in the pancreatic ductal wall. In CPs and PCas, no myofibroblast proliferation was observed at the stenotic portion. The proliferation of myofibroblasts might occur as a wound healing process in FP, while acting against elevation of intraductal pressure in VPCa. In conclusion, proliferation of myofibroblasts plays an important role in ductal changes in various pathological situations.

Actins↗
PubMed2005

The expression and function of the endothelin system in contractile properties of vaginal myofibroblasts of women with uterovaginal prolapse.

OBJECTIVE: The endothelin-1 system regulates (myo)fibroblast contraction in wound healing. Our aim was to determine endothelin-1 system expression and function in contractile properties of vaginal myofibroblasts of women with uterovaginal prolapse. STUDY DESIGN: Cultures of alpha-smooth muscle actin-positive myofibroblasts that were established at the time of repair surgery for prolapse (n = 30; mean age, 56 +/- 14 years) were analyzed and compared for their expression of the endothelin-1 system and contractile properties to myofibroblasts from primiparous women. RESULTS: Myofibroblasts expressed the complete endothelin system but did not secrete endothelin-1. Endothelin-1 binding was mediated exclusively by the endothelin B-receptor. In 3-dimensional collagen gels, spontaneous contraction of myofibroblasts from estrogen-treated women with prolapse was statistically significantly lower than from young primiparous women. Exogenous addition of endothelin-1 decreased the spontaneous contraction of myofibroblasts. CONCLUSION: Genital myofibroblasts of women with uterovaginal prolapse are poorly contractile, and endothelin-1 further decreases vaginal myofibroblast contraction, which is opposite to observations in skin myofibroblasts.

Actins↗
PubMed2000

Role of wound healing myofibroblasts on re-epithelialization of human skin.

In human skin, large burned surfaces heal using two concomitant phenomena: re-epithelialization and dermal neoformation. Numerous studies report the role of interactions between keratinocytes and fibroblasts, but the relationship between wound healing myofibroblasts and keratinocytes is not clear, even though these two cell types coexist during healing. We investigated the influence of myofibroblasts on keratinocyte growth and differentiation using an in vitro skin model. A histological study was performed to determine the speed and quality of epithelialization. When the dermis was populated with fibroblasts, a continuous epidermis was formed in 7-10 days. In contrast, with wound healing myofibroblasts or without cell in dermis, the complete reepithelialization never occurred over the 10-day period studied. After 7 further days of epidermal differentiation, histology showed an epidermis more disorganized and expression of basement membrane constituents was reduced when wound healing myofibroblasts or no cells were added in the dermis instead of fibroblasts. These results suggest that wound healing myofibroblasts are not efficient to stimulate keratinocyte growth and differentiation. Treatment of fibroblasts with TGFbeta1 induced an increase of epidermal cell differentiation as seen when myofibroblasts were present. However, this cytokine did not change re-epithelialization rate and induced an increase of basement membrane matrix deposition in opposition to myofibroblasts. Thus, TGFbeta1 action is not sufficient to explain all the different keratinocyte reactions towards fibroblasts and wound healing myofibroblasts. Our conclusion is that myofibroblasts seem to have a limited role in the re-epithelialization process and might be more associated with the increased extracellular matrix secretion.

Basement Membrane↗
PubMed2006

Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines.

Myofibroblasts and cytokines such as transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor (PDGF)-B have been found to play an important role in pancreatitis-associated fibrogenesis. It is still unclear, however, where in the inflamed pancreas and when these fibrogenic cells and cytokines can be detected. In this study we examined pancreatic tissue from patients with alcoholic chronic pancreatitis to determine the localization and distribution of myofibroblasts and the expression of cytokines in relation to the tissue damage and the activity of the inflammatory process. In tissue from pancreatic specimens from 59 patients with alcoholic chronic pancreatitis the inflammatory process was histologically staged. Myofibroblasts and the cytokines latency-associated peptide, a TGF-beta propeptide, TGF-beta receptor II, PDGF-B and the alpha-isoform of the PDGF receptor were immunohistochemically identified in 10 selected cases representing the four defined stages of alcoholic chronic pancreatitis. In stage I, the stage with overt tissue injury, myofibroblasts were numerous and especially associated with macrophages around areas of necrosis. In stage II, the stage with cellular fibrosis, myofibroblasts were the main component of the interlobular tissue. In stage III, the stage with dense fibrosis, myofibroblasts were rare, and in stage IV, when calculi were present, myofibroblasts were only detected adjacent to duct ulcerations caused by calculi. Latency-associated peptide and TGF-beta receptor II as well as PDGF-B and PDGF receptor-alpha were mainly expressed by macrophages, myofibroblasts and epithelial cells in stages I and II. The results suggest that the fibrogenic process in alcoholic chronic pancreatitis is initiated by a cytokine-based interplay of macrophages and myofibroblasts that follows tissue injury.

Adult↗
PubMed2001

Myofibroblastic differentiation in malignant fibrous histiocytoma (pleomorphic myofibrosarcoma): a clinicopathological study.

AIMS: We compared the clinical and pathological features of pleomorphic malignant fibrous histiocytoma (MFH)-like soft tissue sarcomas with and without myofibroblastic differentiation on electron microscopy. METHODS AND RESULTS: Fifty-three soft tissue tumours designated as MFH by light and electron microscopy were reassessed. Eighteen were specifically diagnosed and excluded, and follow-up (FU) information obtained for 24 of the other 35 cases. Myofibroblastic ultrastructure was seen in 7/24 (29%). Seventeen of 24 (71%) lacked myofibroblasts on electron microscopy, which showed fibroblastic or undifferentiated cells. Histologically, all tumours but one had storiform-pleomorphic areas; one myofibroblastic neoplasm was fascicular and myxoid. No other morphological differences were seen. In seven myofibroblastic cases, smooth muscle in four cases and muscle-specific actin in two cases, desmin in three cases and S100 in one case were present. In 15 other tumours, smooth muscle in five cases and muscle-specific actin in one case, and desmin in one case were present; none of these cases expressed S100. CD34 was found in the myxoid areas of one myofibrosarcoma and 3/15 other tumours. Positivity for bcl-2 was seen only in non-myofibroblastic sarcomas (4/14). On follow-up (median 41 months), 2/7 (29%) myofibroblastic tumours recurred, 5/7 (71%) metastasized, and 3/7 (43%) patients died of disease. Among the non-myofibroblastic sarcomas, with a median follow-up of 47 months, 6/17 cases (35%) recurred, 10/17 (59%) metastasized, and 7/17 patients (41%) died of disease. CONCLUSIONS: Pleomorphic sarcomas with and without myofibroblastic differentiation on electron microscopy are clinically and histologically similar. The former display myoid immunohistochemical markers more frequently.

Adult↗
PubMed1996

Myofibroblasts differentiate from fibroblasts when plated at low density.

Myofibroblasts, defined by their expression of smooth muscle alpha-actin, appear at corneal and dermal incisions and promote wound contraction. We report here that cultured fibroblasts differentiate into myofibroblasts by a cell density-dependent mechanism. Fibroblasts seeded at low density (5 cells per mm2) produced a cell culture population consisting of 70-80% myofibroblasts, 5-7 days after seeding. In contrast, fibroblasts seeded at high density (500 cells per mm2) produced cultures with only 5-10% myofibroblasts. When the myofibroblast-enriched cultures were subsequently passaged at high density, the smooth muscle alpha-actin phenotype was lost within 3 days. Furthermore, initially 60% of the low density-cultured cells incorporated BrdUrd compared to 30% of cells passaged at high density. Media from myofibroblast-enriched cultures had more latent and active transforming growth factor beta (TGF-beta) than did media from fibroblast-enriched cultures. Although there was a trend towards increased numbers of myofibroblasts after addition of exogenous TGF-beta, the results did not reach statistical significance. We conclude that myofibroblast differentiation can be induced in fibroblasts by plating at low density. We propose a cell density-dependent model of myofibroblast differentiation during wounding and healing in which at least two factors interact: loss of cell contact and the presence of TGF-beta.

Actins↗
PubMed2003

Skeletal myosin heavy chain function in cultured lung myofibroblasts.

Myofibroblasts are unique contractile cells with both muscle and nonmuscle properties. Typically myofibroblasts are identified by the expression of alpha smooth muscle actin (ASMA); however some myofibroblasts also express sarcomeric proteins. In this study, we show that pulmonary myofibroblasts express three of the eight known sarcomeric myosin heavy chains (MyHCs) (IIa, IId, and embryonic) and that skeletal muscle myosin enzymatic activity is required for pulmonary myofibroblast contractility. Furthermore, inhibition of skeletal myosin activity and myofibroblast contraction results in a decrease in both ASMA and skeletal MyHC promoter activity and ASMA protein expression, suggesting a potential coupling of skeletal myosin activity and ASMA expression in myofibroblast differentiation. To understand the molecular mechanisms whereby skeletal muscle genes are regulated in myofibroblasts, we have found that members of the myogenic regulatory factor family of transcription factors and Ca(2+) - regulated pathways are involved in skeletal MyHC promoter activity. Interestingly, the regulation of skeletal myosin expression in myofibroblasts is distinct from that observed in muscle cells and suggests that cell context is important in its control.

Animals↗
PubMed1998

Myofibroblasts and the progression of crescentic glomerulonephritis.

BACKGROUND: The cellular and humoral factors involved in the pathogenesis of glomerulosclerosis and renal fibrosis following a crescentic glomerulonephritis have not been fully elucidated. Myofibroblasts and transforming growth factor-beta (TGF-beta) have been implicated in the development of experimental and clinical renal fibrosis. We have attempted to identify these mediators in crescentic glomerulonephritis and determine their role in the progression of the disease. PATIENTS AND METHODS: We studied retrospectively 21 patients with crescentic and necrotizing glomerulonephritis (CNG) with emphasis on the renal expression (detected by immunohistochemistry) of myofibroblasts (alpha-smooth muscle actin+ cells), TGF-beta and collagen (III and IV) as well as their relationship with the clinical outcome of these patients. In situ hybridization histochemistry was applied to determine the site of synthesis of TGF-beta1 and collagen III. All the patients were treated by immunosuppression and followed up for a median period of 14 months. RESULTS: Myofibroblasts and TGF-beta were detected in the crescents as well as in the periglomerular and tubulointerstitial areas in CNG biopsies. TGF-beta1 was also detected within renal tubular cells. The percentage of glomeruli with fibrotic and fibrocellular crescents was positively correlated with the severity of Bowman's capsule disruption (r = 0.631, P < 0.01) and with the intensity of myofibroblast expression in the interstitium (r = 0.504, P < 0.05). Strong interstitial immunostain for myofibroblasts and TGF-beta was also noted in association with interstitial fibrosis. In situ hybridization revealed the site of synthesis of TGF-beta1 to be the renal tubular cells of patients with CNG. By contrast, the site of synthesis of collagen III appeared to be confined to interstitial cells surrounding vessels, tubules and the glomeruli in a distribution identical to that of myofibroblasts. There was a significant positive correlation between the number of interstitial alpha-SMA+ cells and both interstitial TGF-beta (r = 0.591, P < 0.01) and interstitial collagen IV (r = 0.588, P < 0.01). In addition, the number of interstitial alpha-SMA+ cells and the extent of immunostain for collagen IV were positively correlated with the final serum creatinine (r = 0.517, P < 0.05 and r = 0.612, P < 0.01 respectively) and partially predicted functional outcome (R2 = 26.7% and 37.5% respectively) as well as the response to treatment. An association was observed between periglomerular myofibroblasts and the generation of fibrotic and fibrocellular crescents. CONCLUSION: These observations suggest a causal link between myofibroblasts and fibrotic crescent formation. We also believe that interstitial myofibroblasts are actively involved in the pathogenesis of interstitial fibrosis in CNG.

Actins↗
PubMed2005

HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis.

Pulmonary fibrosis is characterized by a loss of lung epithelial cells, replaced by interstitial myofibroblasts to deposit extracellular matrix (ECM) proteins. Previous studies demonstrated that hepatocyte growth factor (HGF) improved lung fibrosis in murine models, whereas molecular mechanisms whereby HGF improved lung fibrosis have yet to be fully understood. When MRC-5 human lung fibroblasts were treated with transforming growth factor-beta1, the cells underwent phenotypic change similar to myofibroblasts and this was associated with up-regulation of c-Met/HGF receptor expression. For the myofibroblast-like cells, HGF increased activities of MMP-2/-9, predominant enzymes for breakdown of fibronectin (FN). Under such conditions, HGF induced caspase-dependent apoptosis, linked with a decrease in a FN central cell binding (CCB) domain involved in FAK phosphorylation. When MMI270 (a broad-spectrum MMP inhibitor) was added together with HGF, decreases in FN-CCB domain expression and FAK phosphorylation by HGF were restored, and these events were associated with an inhibition of HGF-induced apoptosis, suggesting that increased activities of MMPs underlie the major mechanism of HGF-mediated apoptosis in myofibroblasts. In bleomycin-treated mice, c-Met expression was found on interstitial myofibroblasts and HGF increased apoptosis in culture of myofibroblasts isolated from bleomycin-treated murine lungs. Furthermore, administration of recombinant HGF to bleomycin-treated mice increased lung MMP activities and enhanced myofibroblast apoptosis, while in vivo MMI270 injections together with HGF inhibited such MMP activation, leading to suppressed myofibroblast apoptosis. In conclusion, we identified HGF as a key ligand to elicit myofibroblast apoptosis and ECM degradation, whereas activation of the HGF/c-Met system in fibrotic lungs may be considered a target to attenuate progression of chronic lung disorders.

Actins↗
PubMed1982

The spatial and temporal quantification of myofibroblasts.

The number and distribution of myofibroblasts in porcine excisional wounds have been measured over a 16-week period by immunoperoxidase labeling of the smooth-muscle antigen in the cytoplasm of the contractile fibroblasts. Changes in the number of myofibroblasts over time correlate with the rate of wound contraction, and the myofibroblasts were distributed throughout the granulation tissue. These findings support the proposal that the contractile fibroblast is the agent of wound contraction. Significantly fewer myofibroblasts are found near the base of the wound and a larger number of myofibroblasts are found in close proximity to inflammatory foci, suggesting a causal relationship between inflammation and the acquisition of contractile properties by the wound fibroblast. There is evidence of a slightly lower percentage of myofibroblasts in areas of rapid fibroblast replication, and the percentage of myofibroblasts does not vary with changes in the tension across a wound. The immunoperoxidase-staining technique permits the identification of individual myofibroblasts by light microscopy and will be a useful tool for further studies of myofibroblast activity and control.

Animals↗
PubMed2003

Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells.

PURPOSE OF REVIEW: Emerging evidence suggests that tubular epithelial-myofibroblast transdifferentiation is an important event in renal tubulointerstitial fibrosis. This review describes the recent findings in the context of the tubular epithelial-myofibroblast transdifferentiation process and discusses the possible mechanisms involved. RECENT FINDINGS: Tubular epithelial-myofibroblast transdifferentiation is a complex process involving disruption of polarized tubular epithelial cell morphology into cells with spindle-shaped mesenchymal morphology, formation of actin stress fibers, loss of cell-cell adhesions through downregulation of E-cadherin, destruction of basement membrane, and increased cell migration and invasion. This phenotypic transition has also been recently reported in human glomerulonephritis with progressive tubulointerstitial fibrosis. Transforming growth factor-beta is a key fibrogenic growth factor that regulates tubular epithelial-myofibroblast transdifferentiation, which is counter-regulated by hepatocyte growth factor. In addition, basic fibroblast growth factor, advanced glycation end products, and angiotensin II have also been reported to induce the process. Importantly, the recent discovery of transforming growth factor-beta/Smad signaling has allowed the delineation of the intracellular mechanisms of tubular epithelial-myofibroblast transdifferentiation. Indeed, Smad signaling is a key pathway whereby transforming growth factor-beta and angiotensin II induce tubular epithelial-myofibroblast transdifferentiation in vitro. This involves the activation of transforming growth factor-beta receptor-associated Smad2 and is inhibited by an inhibitory Smad protein, Smad7. Thus, Smad signaling plays a critical role in tubular epithelial-myofibroblast transdifferentiation. SUMMARY: Renal myofibroblasts may be derived from tubular epithelial cells by a process of tubular epithelial-myofibroblast transdifferentiation. Transforming growth factor-beta signals through Smads to positively or negatively regulate this process. Blockade of this process by either hepatocyte growth factor or targeting the Smad signaling pathway may provide novel therapeutic strategies to combat renal fibrosis.

Actins↗
PubMed1997

Interstitial myofibroblasts: predictors of progression in membranous nephropathy.

AIMS: To determine the role of interstitial myofibroblasts in the progression of membranous nephropathy; and to assess the predictive value of quantifying myofibroblasts in determining long term renal outcome. METHODS: All cases of membranous nephropathy, diagnosed by renal biopsy at University Hospital of South Manchester between 1984 and 1987, were studied retrospectively. The biopsy specimens (n = 26) were reviewed and analysed morphometrically to measure interstitial volume as a proportion of the total volume of renal cortex, and numbers of interstitial myofibroblasts (cells positive for alpha-smooth muscle actin within the interstitium). Clinical data, with a follow up of seven to eight years, was available for 24 patients, and renal outcome was correlated with pathological changes in the initial diagnostic biopsy specimen. RESULTS: The number of myofibroblasts and interstitial volume were inversely correlated with creatinine clearance at the initial biopsy, and at the end of follow up. Percentage sclerosed glomeruli or stage of glomerular disease, assessed by electron microscopy, did not correlate with renal function at initial biopsy or during follow up. The number of myofibroblasts, but not interstitial volume, correlated with severity of proteinuria at initial biopsy. Of 15 biopsy specimens showing no or mild interstitial fibrosis, four showed a notable increase in the number of interstitial myofibroblasts. All of these patients developed chronic renal failure, compared with three of 11 patients whose specimens showed no or a mild increase in myofibroblast numbers. CONCLUSIONS: Interstitial myofibroblasts play a role in the development of interstitial fibrosis and progressive renal failure in membranous nephropathy. Increased numbers of myofibroblasts in biopsy specimens showing only mild fibrosis may predict subsequent chronic renal failure.

Actins↗
PubMed2002

Differential expression of TGF-beta isoforms by normal and inflammatory bowel disease intestinal myofibroblasts.

Intestinal strictures are frequent in Crohn's disease but not ulcerative colitis. We investigated the expression of transforming growth factor (TGF)-beta isoforms by isolated and cultured primary human intestinal myofibroblasts and the responsiveness of these cells and intestinal epithelial cells to TGF-beta isoforms. Normal intestinal myofibroblasts released predominantly TGF-beta(3) and ulcerative colitis myofibroblasts expressed both TGF-beta(1) and TGF-beta(3), whereas in myofibroblast cultures from fibrotic Crohn's disease tissue, there was significantly lower expression of TGF-beta(3) but enhanced release of TGF-beta(2). These distinctive patterns of TGF-beta isoform release were sustained through several myofibroblast passages. Proliferation of Crohn's disease myofibroblasts was significantly greater than that of myofibroblasts derived from normal and ulcerative colitis tissue. In contrast to cells from normal and ulcerative colitis tissue, neutralization of the three TGF-beta isoforms did not affect the proliferation of Crohn's disease intestinal myofibroblasts. Studies on the effect of recombinant TGF-beta isoforms on epithelial restitution and proliferation suggest that TGF-beta(2) may be the least effective of the three isoforms in intestinal wound repair. In conclusion, the enhanced release of TGF-beta(2) but reduced expression of TGF-beta(3) by Crohn's disease intestinal myofibroblasts, together with their enhanced proliferative capacity, may lead to the development of intestinal strictures.

Actins↗
PubMedDate not supplied

Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast.

The purpose of this study was to investigate the distribution of CD34-positive fibroblasts and alpha-smooth muscle actin (alpha-SMA)-reactive myofibroblasts in the stroma of benign and malignant breast lesions and, secondly, to determine whether the presence of stromal myofibroblasts is associated with some of the clinicopathological characteristics of patients with invasive ductal carcinoma. The presence of stromal CD34-positive fibroblasts and myofibroblasts was investigated (as defined immunohistochemically) in 8 normal breast tissue samples, 58 invasive ductal carcinomas, 9 ductal carcinomas in situ and 16 specimens with benign lesions of the breast (fibroadenomas, ductal hyperplasias). We further studied the correlations between the presence of stromal myofibroblasts with 7 clinicopathological parameters in 58 invasive ductal carcinomas. The results indicated that the stroma of normal breast tissues contained CD34-positive fibroblasts. All benign breast lesions exhibited stromal CD34-positive fibroblasts. In contrast, the stroma of ductal carcinomas showed a complete loss of CD34-positive fibroblasts. alpha-SMA expression in stromal fibroblasts (myofibroblasts) was not detected in normal tissue samples or benign lesions except in 1 case of fibroadenoma, whereas positive myofibroblasts were found in 44.4% of ductal carcinomas in situ and 56.9% of invasive breast carcinomas. Comparison of clinicopathological parameters between invasive ductal carcinomas with and without stromal myofibroblasts revealed significant differences in lymph node metastasis, high histological grade and high microvessel density. These results suggest that CD34 loss and the presence of myofibroblasts favor the diagnosis of breast carcinoma. In invasive ductal carcinoma, the presence of stromal myofibroblasts correlated significantly with pathological parameters associated with a poor prognosis.

Adult↗
PubMed2006

Electrotonic modulation of cardiac impulse conduction by myofibroblasts.

Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express alpha-smooth muscle actin (alphaSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [theta] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to alphaSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected theta and dV/dtmax in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both theta and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), theta fell <200 mm/s. This biphasic dependence of theta and dV/dtmax on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from -78 mV to -50 mV as measured using microelectrode recordings. These findings suggest that myofibroblasts, apart from their role in structural remodeling, might contribute to arrhythmogenesis by direct electrotonic modulation of conduction and that prevention of their appearance might represent an antiarrhythmic therapeutic target.

Animals↗