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PubMed2002

Immunohistochemical distribution of epithelioid cell, myofibroblast, and transforming growth factor-beta1 in the granuloma caused by Mycobacterium avium intracellulare complex pulmonary infection.

The present study was designed to evaluate the distribution of epithelioid cells, myofibroblasts, and TGF-beta1 in the formation of granuloma caused by Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed for 9 cases of positive MAC culture in which lung resections were performed between January 1989 and August 1999. Resected lung specimens were evaluated histologically and immunohistochemically for CD68 (stain for monocytes and macrophages, and epithelioid cells) and alpha-smooth muscle actin as well as vimentin (stain for myofibroblasts), and TGF-beta1 was performed. When granuloma was initially formed, no myofibroblasts were found, but as caseous necrosis appeared, the thin epithelioid cell layer was detected and the outer myofibroblast layer gradually became thick. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and was associated with the outer layer of myofibroblasts. In addition, the anti-TGF-beta1 antibody stained the cytoplasm of epithelioid cells and multinucleated giant cells, preceding the advent of myofibroblasts. In summary, our present study evaluated distributions of epithelioid cells, myofibroblasts, and TGF-beta along with the morphogenesis of granuloma, and clearly demonstrated the immunohistochemical difference between granuloma with caseous necrosis and granulomas without caseous necrosis.

Actins↗
PubMed2001

Perivascular responses after angioplasty which may contribute to postangioplasty restenosis: a role for circulating myofibroblast precursors?

These studies suggest that the adventitia may play a role in vascular lesion formation after balloon overstretch injury of pig coronary arteries by contributing to the cellular mass of the neointima and the synthesis of growth factors. In addition, the adventitia may contribute to vascular remodeling and constriction of the external elastic lamina through accumulation of myofibroblasts containing alpha smooth muscle actin in the adventitia surrounding the injury site. Inhibition of myofibroblast proliferation and/or recruitment by intravascular brachytherapy positively affects vascular remodeling through its action on adventitial cells. Inflammation is a major event associated with balloon angioplasty, resulting in the sequential recruitment of neutrophils (2-24 hours) and monocyte/macrophages (24-72 hours) predominantly into the adventitia surrounding the injury site. It is hypothesized that inflammatory cells release cytokines and/or increase the production of superoxides which stimulate the proliferation and recruitment of adventitial myofibroblasts. Inflammatory and proliferative responses were not confined to the local adventitia but were found extending as far as 1-3 mm away from the injured vessel in the distal perivascular tissues. Studies were performed to examine the expression of genes associated with cell migration at early times after injury in an attempt to determine the source of the adventitial myofibroblasts. Expression of genes involved in cell migration including MMP-2, MMP-9, and tenascin was found as early as 2 hours following angioplasty in the intramyocardial, pericardial, and adipose tissue fibroblasts. While these studies suggest that local tissue was the source of the myofibroblasts recruited to the injury site, we have been unable to confirm this finding by direct fluorescent labeling of adventitial cells. Recent work from our laboratory suggests that myofibroblast precursors may be isolated from buffy coat preparations from peripheral blood. These results lead us to hypothesize that stem cells that differentiate into myofibroblasts may be recruited in early inflammatory infiltrates in the adventitia. Clearly, additional work will have to be directed at a more detailed examination of the response of adventitial and other perivascular cells and tissues to balloon injury to determine their sources and their role in regulating vascular lesion development.

Angioplasty↗
PubMed2005

K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts.

Despite the important roles played by ventricular fibroblasts and myofibroblasts in the formation and maintenance of the extracellular matrix, neither the ionic basis for membrane potential nor the effect of modulating membrane potential on function has been analyzed in detail. In this study, whole cell patch-clamp experiments were done using ventricular fibroblasts and myofibroblasts. Time- and voltage-dependent outward K(+) currents were recorded at depolarized potentials, and an inwardly rectifying K(+) (Kir) current was recorded near the resting membrane potential (RMP) and at more hyperpolarized potentials. The apparent reversal potential of Kir currents shifted to more positive potentials as the external K(+) concentration ([K(+)](o)) was raised, and this Kir current was blocked by 100-300 muM Ba(2+). RT-PCR measurements showed that mRNA for Kir2.1 was expressed. Accordingly, we conclude that Kir current is a primary determinant of RMP in both fibroblasts and myofibroblasts. Changes in [K(+)](o) influenced fibroblast membrane potential as well as proliferation and contractile functions. Recordings made with a voltage-sensitive dye, DiBAC(3)(4), showed that 1.5 mM [K(+)](o) resulted in a hyperpolarization, whereas 20 mM [K(+)](o) produced a depolarization. Low [K(+)](o) (1.5 mM) enhanced myofibroblast number relative to control (5.4 mM [K(+)](o)). In contrast, 20 mM [K(+)](o) resulted in a significant reduction in myofibroblast number. In separate assays, 20 mM [K(+)](o) significantly enhanced contraction of collagen I gels seeded with myofibroblasts compared with control mechanical activity in 5.4 mM [K(+)](o). In combination, these results show that ventricular fibroblasts and myofibroblasts express a variety of K(+) channel alpha-subunits and demonstrate that Kir current can modulate RMP and alter essential physiological functions.

Animals↗
PubMed2006

Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis.

Prostaglandins (PG) are produced throughout the gastrointestinal tract and are critical mediators for a complex array of physiologic and pathophysiologic processes in the intestine. Intestinal myofibroblasts, which express cyclooxygenase (COX) and generate PGE(2), play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE(2) activated human intestinal subepithelial myofibroblasts (18Co) through Gs protein-coupled E-prostanoid receptors and the cyclic AMP/protein kinase A pathway. 18Co cells and primary colonic myofibroblast isolates expressed a number of growth factors; several of them were dramatically regulated by PGE(2). An epidermal growth factor-like growth factor, amphiregulin (AR), which was not expressed by untreated cells, was strongly induced by PGE(2). Expression of vascular endothelial growth factor A (VEGFA) was rapidly increased by PGE(2) exposure. Hepatocyte growth factor (HGF) was elevated in PGE(2)-treated myofibroblasts at both mRNA and protein levels. Thus, PGE(2)-activated myofibroblasts promoted the proliferation and migration of intestinal epithelial cells, which were attenuated by neutralizing antibodies to AR and HGF, respectively. Moreover, in the presence of PGE(2), myofibroblasts strongly stimulated the migration and tubular formation of vascular endothelial cells. Neutralizing antibody to VEGFA inhibited the observed stimulation of migration. These results suggest that myofibroblast-generated growth factors are important mediators for PGE(2)-induced intestinal epithelial proliferation and angiogenesis, which play critical roles in intestinal homeostasis, inflammation, and neoplasia.

Cell Culture Techniques↗
PubMed2002

Proliferation of myofibroblasts in the stroma of epithelial hyperplastic lesions and squamous carcinoma of the larynx.

OBJECTIVES: The immunohistochemical phenotype, distribution and significance of proliferation of myofibroblasts in laryngeal epithelial hyperplastic lesions (EHL) and squamous carcinoma (SC) were analyzed. METHODS: Samples of 42 resected larynxes and 40 laryngeal biopsies of EHL and SC were included. Immunohistochemistry was performed using antibodies against vimentin, alpha-smooth muscle actin (SMA), desmin and leukocyte common antigen. RESULTS: Myofibroblasts were vimentin- and SMA-positive, and were found exclusively in SC, indicating that invasion beyond the basement membrane is necessary to evoke a myofibroblastic stromal reaction. We observed two patterns of stromal reaction in SC: one was characterized by a marked proliferation of myofibroblasts and desmoplasia, with scarce lymphocytic infiltration; this pattern tended to be associated with well- or moderately differentiated SC. The other was characterized by few myofibroblasts, weak desmoplasia, and dense lymphocytic infiltration; the latter pattern tended to be associated with moderately or poorly differentiated SC. The degree of myofibroblast proliferation was inversely related to the density of lymphocytic infiltration. Antibodies against SMA also stained stromal blood vessels, demonstrating a gradual increase of vessel density as the grade of EHL increased. CONCLUSIONS: Immunohistochemical analysis of myofibroblasts provides useful information on the phenotypic characteristics of the stroma in laryngeal EHL and SC, and can serve as an additional marker of invasion.

Actins↗
PubMed1996

Transforming growth factor-beta 1 expression and myofibroblast formation during arterial repair.

Transforming growth factor-beta 1 (TGF-beta 1) plays a central role in tissue repair owing to its modulating effects on cell growth and the synthesis of extracellular matrix. We have previously shown that adventitial fibroblasts differentiate to myofibroblasts after endoluminal injury, thereby contributing to arterial remodeling. Since TGF-beta 1 exerts several biologic actions attributed to myofibroblasts, we examined its role in myofibroblast formation in a porcine model of balloon overstretch coronary artery injury. TGF-beta 1 transcripts were induced in numerous adventitial cells 2 days after injury (47 +/- 10%, P < .001 versus control). These cells displayed no smooth muscle (SM) markers, i.e., alpha-SM actin or desmin, which suggested their fibroblastic origin. This was further corroborated by the rare presence of macrophages in the injured adventitia (3 +/- 1%). At 7 to 8 days, most TGF-beta 1-expressing cells demonstrated alpha-SM actin immunoreactivity. Their myofibroblast phenotype was confirmed by electron microscopy, which revealed microfilaments (stress fibers) and a well-developed rough endoplasmic reticulum. The distribution of TGF-beta 1 transcripts by in situ hybridization was paralleled by the immunolocalization of intracellular and extracellular TGF-beta 1 epitopes. At later times (> 14 days after injury), the decrease in TGF-beta 1 coincided with the disappearance of adventitial myofibroblasts, whereas the neointima exhibited longer TGF-beta 1 expression. In conclusion temporal and spatial relationships between TGF-beta 1 and myofibroblast formation suggest an important role for autocrine TGF-beta 1 in the phenotypic modulation of vascular fibroblasts. Induction of TGF-beta 1 expression may provide a differentiation signal for adventitial fibroblasts to become myofibroblasts, which affect arterial remodeling via their mechanical and synthetic properties.

Animals↗
PubMed2002

Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts.

The aim of the present study was to elucidate how transforming growth factor-beta(1) (TGF-beta(1)) can stimulate collagen deposition in cardiac tissue by interstitial cells via stimulation of fibroblasts, via myofibroblasts, or via differentiation of fibroblasts to myofibroblasts. The dose- and time-dependent stimulation of collagen production and of expression of alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts, was studied in cultures of second-passage adult rat cardiac fibroblasts. The TGF-beta(1)-stimulated collagen production is positively correlated (r=0.68, P<0.001) with the appearance of alpha-SMA. Only at high concentrations (40 to 600 pmol/L) and after a long time (24 to 48 hours) of incubation, TGF-beta(1) increases the collagen production and stimulates the differentiation of fibroblasts to myofibroblasts. The maximal stimulation of the collagen production (2-fold, P<0.001) observed after incubation of cultures of fibroblasts with 600 pmol/L TGF-beta(1) for 48 hours is accompanied by a maximal stimulation of alpha-SMA expression (3.5-fold, P<0.001), when cultures consist mainly of myofibroblasts. The stimulation of collagen production cannot be reversed either after additional incubation of TGF-beta(1)-stimulated second-passage cultures for 2 days or in their offspring in the next third passage after incubation for 7 days without TGF-beta(1). The increased collagen production in these third-passage cultures cannot be further stimulated by TGF-beta(1). Our data suggest that TGF-beta(1)-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of the collagen production either in fibroblasts or in myofibroblasts. Instead, TGF-beta(1) induces the differentiation of fibroblasts to myofibroblasts, which have a higher activity for collagen production than fibroblasts.

Actins↗
PubMed2006

Telomerase regulation of myofibroblast differentiation.

Telomerase activity, which has wide expression in cancerous cells, is induced in lung proliferating fibroblasts. It is preferentially expressed in fibroblasts versus myofibroblasts. It is unknown whether regulation of telomerase expression is related to the process of fibroblast differentiation into myofibroblasts. The objective of this study was to clarify such a potential link between telomerase expression and myofibroblast differentiation. Telomerase inhibitor, 3'-azido-2',3'-dideoxythymidine, or antisense oligonucleotide to the telomerase RNA component was used to inhibit the induced fibroblast telomerase activity. The results showed that inhibition of induced telomerase increased alpha-smooth muscle actin expression, an indicator of myofibroblast differentiation. In contrast, induction of telomerase by basic fibroblast growth factor inhibited alpha-smooth muscle actin expression. These findings suggest that the loss of telomerase activity is closely associated with myofibroblast differentiation and possibly functions as a trigger for myofibroblast differentiation. Conversely, expression of telomerase suppresses myofibroblast differentiation.

Actins↗
PubMed2006

Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts.

Thy-1 is a glycosylphosphatidyl-inositol-linked cell surface glycoprotein whose exact biological role remains unclear. Differential expression of Thy-1 affects fibroblast proliferation and fibrogenic signaling. In idiopathic pulmonary fibrosis, the proliferating myofibroblasts within the fibroblastic foci are Thy-1(-), whereas normal lung fibroblasts are predominantly Thy-1(+). In this study, we used rat lung fibroblasts sorted for Thy-1 expression to examine myofibroblastic differentiation in response to fibrogenic stimuli. We examined the effects of transforming growth factor-beta, endothelin-1, and connective tissue growth factor on the expression of myofibroblast proteins and myogenic regulatory factors by real-time RT-PCR and immunoblotting. Thy-1(-) cells have significantly higher myofibroblast and myogenic regulatory factor gene and protein expression compared with Thy-1(+) cells, confirmed by immunofluorescence. We also used floating collagen matrix contraction assays to assess the functional differentiation of the fibroblasts. At baseline and after stimulation with transforming growth factor-beta and endothelin-1, Thy-1(-) cells caused significantly greater collagen contraction than did Thy-1(+) cells, supporting the hypothesis that Thy-1(-) cells are more fully differentiated myofibroblasts. Because apoptosis has been implicated in the regression of myofibroblasts, we examined the percentage of apoptotic cells in the contracted collagen matrices at baseline and after stimulation with fibrogenic agents. A significantly greater proportion of Thy-1(+) cells underwent apoptosis in all conditions compared with Thy-1(-) fibroblasts. Transfection of Thy-1 into Thy-1(-) cells inhibits collagen matrix contraction and reduces cell survival. Our data indicate that Thy-1 regulates myogenic gene expression, myofibroblastic differentiation, and survival in lung fibroblasts.

Actins↗
PubMedDate not supplied

Immunohistochemical analysis of macrophages, myofibroblasts, and transforming growth factor-beta localization during rat renal interstitial fibrosis following long-term unilateral ureteral obstruction.

Renal interstitial fibrosis was induced in rats by chronic unilateral ureteral obstruction (UUO). To identify the mechanisms behind the fibrosis, macrophage influx, myofibroblast involvement, and the localization of transforming growth factor-beta (TGF-beta, a fibrogenic cytokine) were investigated immunohistochemically in rats euthanatized at 0 (controls), 3, 6, 9, 12, and 15 days after UUO. The number of alpha-smooth muscle actin-positive myofibroblasts began to increase significantly in the medulla from day 3, and the development of medullary fibrosis was confirmed from day 6 by morphometric analysis. From day 9, papillary fibrosis also developed in association with an increased number of myofibroblasts. These myofibroblasts showed a parallel orientation to the mucosal surface of the pelvis. In the medulla and papilla, from day 6 the number of ED1 (primary antibody)-positive macrophages began to increase significantly. There appeared to be a relationship between macrophage influx and myofibroblast involvement. By contrast, in the cortex there was no marked increase in myofibroblasts nor development of fibrotic tissues, regardless of increased number of macrophages from day 6. Immunohistochemically, no staining for TGF-beta was found in infiltrating macrophages or myofibroblasts. However, TGF-beta was localized on some cortical proximal renal tubules both of normal control and obstructed kidneys in the early stages on days 3, 6, and 9, suggesting that the possible origin of TGF-beta may be renal epithelia. However, the staining intensity for TGF-beta on the renal epithelia tended to be weakened in advanced obstructed kidneys on days 12 and 15. The likely contribution of TGF-beta to the advanced stages of UUO-induced renal fibrosis remains to be determined.

Actins↗
PubMed2005

Myofibroblasts in palatal wound healing: prospects for the reduction of wound contraction after cleft palate repair.

The surgical closure of orofacial clefts is considered to impair maxillary growth and dento-alveolar development. Wound contraction and subsequent scar tissue formation, during healing of these surgical wounds, contribute largely to these growth disturbances. The potential to minimize wound contraction and subsequent scarring by clinical interventions depends on the surgeon's knowledge of the events responsible for these phenomena. Fibroblasts initiate wound contraction, but proto-myofibroblasts and mature myofibroblasts are by far the most important cells in this process. Myofibroblasts are characterized by their cytoskeleton, which contains alpha-smooth-muscle actin. Additionally, their contractile apparatus contains bundles of actin microfilaments and associated contractile proteins, such as non-muscle myosin. This contractile apparatus is thought to be the major force-generating element involved in wound contraction. After closure of the wound, the myofibroblasts disappear by apoptosis, and a less cellular scar is formed. A reduction of contraction and scarring might be obtained by inhibition of myofibroblast differentiation, stimulation of their de-differentiation, stimulation of myofibroblast apoptosis, or impairment of myofibroblast function. In this review, we will discuss all of these possibilities, which ultimately may lead to a better outcome of cleft palate surgery.

Animals↗
PubMed2004

Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA.

BACKGROUND: The cytokine leukemia inhibitory factor (LIF) mediates its biological effects through binding to its high affinity receptor made of the low-affinity LIF receptor subunit gp190 (LIF-R) and the gp130 subunit. LIF exerts several important effects in the liver, however, data on liver expression of LIF are scarce. The aim of this study was to examine the expression of LIF and LIF-R in human liver. RESULTS: LIF expression, analyzed by immunohistochemistry, was barely detectable in normal liver but was strong within cirrhotic fibrous septa and was found in spindle-shaped cells compatible with myofibroblasts. Accordingly, cultured human liver myofibroblasts expressed high levels of LIF as shown by ELISA and Northern blot. Biological assay demonstrated that myofibroblast-derived LIF was fully active. RT-PCR showed expression of the LIF-D and M isoforms, and also of low levels of new variants of LIF-D and LIF-M resulting from deletion of exon 2 through alternative splicing. LIF receptor expression was detected mainly as a continuous sinusoidal staining that was enhanced in cirrhotic liver, suggestive of endothelial cell and/or hepatocyte labeling. Immunohistochemistry, flow cytometry and STAT-3 phosphorylation assays did not provide evidence for LIF receptor expression by myofibroblasts themselves. LIF secretion by cultured myofibroblasts was down regulated by the addition of interleukin-4. CONCLUSIONS: We show for the first time the expression of LIF in human liver myofibroblasts, as well as of two new isoforms of LIF mRNA. Expression of LIF by myofibroblasts and of its receptor by adjacent cells suggests a potential LIF paracrine loop in human liver that may play a role in the regulation of intra-hepatic inflammation.

Journal Article↗
PubMed2004

IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal.

The development of idiopathic pulmonary fibrosis (IPF) is associated with myofibroblast accumulation and collagen deposition in the lung parenchyma. Recent studies have suggested that the fibroproliferative response is associated with immune deviation toward a T helper cell type 2 (Th2) cytokine profile. In addition, myofibroblast accumulation may be the result of resistance to physiologic apoptosis. If and how these events are linked remain largely unknown. Insulin-like growth factor-I (IGF-I) is a fibroblast growth and survival factor that has long been implicated in the pathogenesis of IPF. We have previously shown that interstitial macrophage-derived IGF-I correlates with disease severity in IPF, and the Th2 cytokines interleukin (IL)-4 and IL-13 stimulate the expression and secretion of IGF-I by macrophages. In the present study, we tested the hypothesis that IL-4-induced, macrophage-derived IGF-I protects myofibroblasts from apoptosis. Using a growth factor withdrawal model of apoptosis in the myofibroblast cell line, CCL39, we demonstrate that conditioned media from IL-4-stimulated macrophages protect myofibroblasts from apoptosis. The survival effect is lost when IGF-I is immunodepleted from macrophage-conditioned media with IGF-I-specific antibodies. We also show that the protection of myofibroblasts by macrophage-derived IGF-I correlates with and is dependent on the activation of the prosurvival kinases Akt and extracellular signal-regulated kinase. These findings support the view that IL-4-stimulated, macrophage-derived IGF-I may contribute to the persistence of myofibroblasts in pulmonary fibrosis in the Th2-deviated environment of the fibrotic lung.

Animals↗
PubMed2000

Role of myofibroblasts during normal tissue repair and excessive scarring: interest of their assessment in nephropathies.

Following injury, tissue repair process takes place involving inflammation, granulation tissue formation and scar constitution. Granulation tissue develops from the connective tissue surrounding the damaged area and contains vessels, inflammatory cells, fibroblasts and myofibroblasts. Myofibroblasts play an important role in many tissue injuries and fibrocontractive diseases. The process of normal wound repair after tissue injury follows a closely regulated sequence including the activation and the proliferation of fibroblastic cells. In pathological situations, the normal resolution stages are abrogated and the proliferation of myofibroblasts continues, inducing excessive accumulation of extracellular matrix. The differentiation of fibroblastic cells into myofibroblasts is an early event in the development of tissue fibrosis. Myofibroblastic cells express smooth muscle cytoskeletal markers (alpha-smooth muscle actin in particular) and participate actively in the production of extracellular matrix. The evaluation of myofibroblast differentiation in renal biopsies would be useful for histopathologists to appreciate the intensity of tissue injury and particularly to predict the long term outcome of some nephropathies. Immunohistochemical studies for alpha-smooth muscle actin should be made systematically in renal tissue biopsies. Myofibroblastic differentiation appears to play a significant role in the progression of renal failure and seems to be a useful marker of progressive disease.

Animals↗
PubMed2002

Role of myofibroblasts at the invasion front.

Tumor progression occurs within a microecosystem, where cancer cells and myofibroblasts exchange proteinases and cytokines that promote growth directly through stimulation of proliferation and survival, as well as invasion through local proteolysis of the extracellular matrix and stimulation of motility. Myofibroblasts maintain the capacity of fibroblasts to induce differentiation. Fibroblasts are the main source of tumor-associated myofibroblasts. The transition to myofibroblasts also occurs in noncancerous situations. This transition is modulated by mechanical stress and cytokines, amongst which transforming growth factor-beta. The cross-talk between cancer cells and myofibroblasts illustrates the microecosystem of tumor invasion. In order to consider myofibroblasts as a possibly new target for cancer therapy, further characterization of the molecular cross-talk between myofibroblasts and cancer cells is required.

Animals↗
PubMed2002

Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps.

CONTEXT: Myofibroblasts are distinct cells with characteristics of both smooth muscle cells and fibroblasts. Through their ability to secrete cytokines, chemokines, prostaglandins, growth factors, and matrix components, they are thought to play critical roles in inflammation, growth, repair, and neoplasia. OBJECTIVE: The goal of this study was to identify the distinct cell populations of the lamina propria of normal colon and colorectal polyps. DESIGN: We studied the expression of alpha-smooth muscle actin (alphaSMA), smooth muscle myosin (SMM), desmin, vimentin, and c-kit by intestinal mesenchymal (stromal) cells in the normal colonic mucosa (n = 5), as well as in hyperplastic polyps (n = 5), sporadic colorectal adenomas (n = 47), and adenomas from patients with familial polyposis (n = 36). RESULTS: In the normal colonic mucosa, the pericryptal stromal cells were alphaSMA+, SMM+, desmin-, and vimentin+, defining them as myofibroblasts. In contrast, cells of the muscularis mucosae were alphaSMA+, SMM+, desmin+, and vimentin-, defining them as smooth muscle cells. alpha-Smooth muscle actin also highlighted direct connections between the muscularis mucosae and the pericryptal myofibroblasts, and vimentin immunostaining showed a network of connections between the alphaSMA+ pericryptal myofibroblasts and the alphaSMA- fibroblasts in the interstitium. In all hyperplastic polyps and adenomatous polyps, the interstitial stromal cells (fibroblasts) now also express alphaSMA and form a syncytium of alphaSMA+ networklike connections throughout the lamina propria. Stromal cells of sporadic adenomas demonstrated the same immunohistochemical staining characteristics displayed by adenomas from patients with familial polyposis and by hyperplastic polyps. Conclusions.-These findings indicate that in normal colon, alphaSMA- fibroblasts are the predominant cell type in the lamina propria. However, the pericryptal (subepithelial) stromal cells are a distinct cell type (alphaSMA+ myofibroblast) that is immunophenotypically different from muscularis mucosae smooth muscle cells and are connected to the interstitial, nonpericryptal fibroblasts with which they exist as a network throughout the lamina propria of the normal colon. Furthermore, in both hyperplastic and neoplastic polyps, there are changes in nonpericryptal fibroblasts from vimentin+, alphaSMA-, and SMM- to vimentin+, alphaSMA+, and SMM+; thus, the interstitial fibroblasts are replaced by myofibroblasts. The factors that cause these changes and the origin of the myofibroblasts need to be determined to clarify the biology of colorectal tumorigenesis.

Adenoma↗
PubMed2001

Transforming growth factor-beta-stimulated connective tissue growth factor expression during corneal myofibroblast differentiation.

PURPOSE: Transforming growth factor beta1 (TGF-beta) stimulates the differentiation of myofibroblasts as indicated by the nascent expression of alpha-smooth muscle (alpha-SM) actin protein and its organization into stress fibers. Downstream messengers of TGF-beta in the conversion from the fibroblast to the myofibroblast phenotype were investigated. Whether TGF-beta increases the transcription of a second growth factor, connective tissue growth factor 1 (CTGF), which could mediate myofibroblast differentiation, was evaluated. CTGF, a newly identified growth factor, is highly expressed in dermal granulation tissue. METHODS: In this study, primary cultures of rabbit corneal fibroblasts were exposed to growth factors to investigate CTGF mRNA and protein expression during myofibroblast differentiation. Statistical analysis was used to evaluate the impact of growth factor treatment on myofibroblast differentiation. RESULTS: . TGF-beta treatment induced both CTGF mRNA and protein in rabbit corneal fibroblasts; in contrast, fibroblast growth factor-2 (FGF) and heparin led to a decrease in CTGF mRNA. Addition of recombinant CTGF to rabbit corneal fibroblast cultures did not significantly increase alpha-SM actin mRNA or protein nor did it appear to affect assembly of alpha-SM actin stress fibers. CONCLUSIONS: This is the first study to present evidence for the induction of CTGF by TGF-beta treatment of corneal fibroblasts. It is doubtful that CTGF is the TGF-beta mediator of the corneal fibroblast to myofibroblast transition because CTGF does not induce alpha-SM actin in subconfluent fibroblast cultures. CTGF may play a supporting role in myofibroblast differentiation.

Actins↗
PubMed2001

Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression.

Myofibroblastic invasion associated with malignant epithelial cells of endometrial cancer as well as other cancers is often found in the interstitium. To assess the myofibroblastic-epithelial interaction, frozen sections from a total of 10 endometrial cancers with or without invasive myofibroblasts were immunohistochemically examined. Interestingly, the invasive myofibroblasts adjacent to malignant epithelial cells showed frequently intensive positive staining of several growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor I, and epidermal growth factor, the cognate receptors such as Fetal liver kinase-1/Kinase Insert Domain-containing receptor/VEGF receptor-2, fms-like tyrosine kinase-1/VEGF receptor-1, and epidermal growth factor receptor, several cell cycle regulators such as cyclins and cyclin dependent kinases, and estrogen receptor alpha. Moreover, we indicated that the majority of the myofibroblasts as well as cancer epithelial cells are proliferating because of their positive staining of proliferating cell nuclear antigen and Ki-67. Furthermore, the myofibroblasts were also positive of hypoxia-inducible factor 1 alpha, which is a marker protein of hypoxia, probably followed by activation of VEGF-Flk-1 and VEGF-fms-like tyrosine kinase-1 signals, which could initiate angiogenesis. These findings suggest directly that the myofibroblasts might participate in the progression of tumor cells in terms of cancer cell growth stimulation and also activated initiation of angiogenesis.

Adult↗