Giulio Gabbiani

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• MD, PhD
• Professor Emeritus at University of Geneva

The term fibra was originally equivalent to the present term “lobe” (from the Latin lobus). The modern use of fibra, as an elongated and thin structure, applied to muscle, nerves, ligaments, tendons, and small vessels, begins with Andreas Vesalius (1514–64) and Gabriele Falloppia (1523–62). Marie François Xavier Bichat (1771–1802) was the first to...

Fibrotic diseases were all first clearly described between the late 18th and the 19th century. Noël Retz (1758–1810) in 1790 gave the earliest recognizable description of a keloid. “Dupuytren disease” was thoroughly described by Guillaume Dupuytren (1777–1835) in 1831. A first case of myocardial fibrosis was reported by Giovanni Battista Morgagni (...

The first description of myofibroblast dated to 1971, and it was based on the presence of microfilament bundles in granulation tissue fibroblasts.

A Mesopotamian clay tablet that dates to 2200 BC describes, perhaps for the first time, a 4-step approach to wound care. John Hunter (1728–93) understood the importance of granulation tissue formation in the repair process and that granulating was the consequence of inflammation. Franz Joseph Lang (1894–1975) advanced that macrophages arise from lo...

Myofibroblasts are key cells in mediating normal wound contraction and promoting connective tissue deformations characteristic of fibrosis and scarring. Five decades ago, myofibroblasts were discovered in electron micrographs of wound granulation tissue as fibroblastic cells containing microfilaments that are organized in bundles like those present...

Fascial tissues form a ubiquitous network throughout the whole body, which is usually regarded as a passive contributor to biomechanical behavior. We aimed to answer the question, whether fascia may possess the capacity for cellular contraction which, in turn, could play an active role in musculoskeletal mechanics. Human and rat fascial specimens f...

Background: Culprit coronary atherosclerotic plaques (APs) from young sudden cardiac death (SCD) victims are mostly non-atheromatous, i.e., consisting of proliferative smooth muscle cells (SMCs). Coronary vasospasm has been advocated to explain plaque instability in the absence of thrombosis. Our aim was to characterize the SMC phenotype in the in...

Higher vertebrates (mammals and birds) express six different highly conserved actin isoforms that can be classified in three subgroups: 1) sarcomeric actins, α-skeletal (α-SKA) and α-cardiac (α-CAA), 2) smooth muscle actins (SMAs), α-SMA and γ-SMA, and 3) cytoplasmic actins (CYAs), β-CYA and γ-CYA. The variations among isoactins, in each subgroup,...

The discovery of the myofibroblast has allowed definition of the cell responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast and the mechanisms of myofibroblast generation. Myofibroblasts originate from a variety of cells according to the organ and the type of les...

Higher vertebrates express six different highly conserved actin isoforms that can be classified in three subgroups: 1) sarcomeric actins, α-skeletal (α-SKA) and α-cardiac (α-CAA), 2) smooth muscle actins (SMAs), α-SMA and γ-SMA, and 3) cytoplasmic actins (CYAs), β-CYA and γ-CYA. The variations among isoactins, in each subgroup, are due to 3-4 amino...

α-Smooth Muscle Actin (α-SMA), a widely characterized cytoskeletal protein, represents the hallmark of myofibroblast differentiation. Transforming growth factorβ1 (TGFβ1) stimulates α-SMA expression and incorporation into stress fibers, thus providing an increased myofibroblast contractile force that participates in tissue remodeling. We have addre...

Here we discuss how the concept and the name of cytoskeleton were generated and started to evolve over the last two centuries into what is presently a basic topic of modern biology. We also attempt to describe some facets of the emergence of cytoskeleton component characterization in which our laboratory was in part involved. © 2014 Wiley Periodica...

The souvenirs of Hans Selye as a teacher of graduate and post graduate students are presented and discussed. The main aim of his teaching was to orient the student toward importance and originality of findings.

Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased...

Objectives: Characterize the phenotypic features of smooth muscle cells (SMCs) in the wall of human saccular intracranial aneurysms (sIAs). Methods and Results: We investigated by means of immunohistochemistry the expression of the cytoskeletal differentiation markers α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and sm...

Objectives: Characterize the phenotypic features of smooth muscle cells (SMCs) in the wall of human saccular intracranial aneurysms (sIAs). Methods and results: We investigated by means of immunohistochemistry the expression of the cytoskeletal differentiation markers α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and...

The primary function of smooth muscle is to produce the contraction phenomena in the circulatory, respiratory, gastrointestinal, and urogenital systems. However, in the adult organism the smooth muscle cell retains significant proliferative, synthetic, and secretory functions compared to skeletal and cardiac myocytes. The variety of physiological r...

Deregulation of myofibroblast contraction and collagen synthesizing activities underlie the tissue deformities that characterize Dupuytren’s nodules and cords. The same harmful processes are instrumental in the formation of hypertrophic scars as well as organ fibrosis that can ultimately contribute to heart, lung, liver, and kidney failure. Here we...

More than 50 years ago, smooth muscle cells (SMC) of the carotid artery were shown to undergo "de-differentiation" upon ligation injury.(1) Since this classic study, scores of research groups have used a variety of in vivo and in vitro model systems as well as numerous clinical studies to demonstrate the conversion of normally contractile vascular...

The incidence of chronic kidney diseases (CKD) is constantly rising, reaching epidemic proportions in the western world and leading to an enormous threat, even to modern health-care systems, in industrialized countries. Therapies of CKD have greatly improved following the introduction of drugs targeting the renin-angiotensin system (RAAS) but even...

Introduction: Venous abnormalities have been associated with different neurological conditions, and the presence of a vascular involvement in multiple sclerosis (MS) has long been anticipated. In view of the recent debate regarding the existence of cerebral venous outflow impairment in MS due to abnormalities of the azygos or internal jugular vein...

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a prote...

Detailed description of the preliminary experiments performed to (i) verify dose-dependent effects of long-term administration of RSV on functional parameters, and (ii) select the most suitable dose of the compound. (DOC)

Since its first description in wound granulation tissue, the myofibroblast has been recognized to be a key actor in the epithelial-mesenchymal cross-talk that plays a crucial role in many physiological and pathological situations, such as regulation of prostate development, ventilation-perfusion in lung alveoli or organ fibrosis. The presence of my...

Retinoic acid (RA) is a vitamin A derivative that exerts pleiotropic biological effects. Intracellular transport and metabolism of RA are regulated by cellular retinol-binding proteins (CRBP). CRBP-1 is transiently expressed in granulation tissue fibroblasts during wound healing; however, its role in cardiac remodeling remains unknown. A rat myocar...

The myofibroblast, a contractile fibroblastic cell expressing α-smooth muscle actin (α-SMA), has been reported to play a role in ligament healing. The aim of this study was to evaluate the feasibility of transplanting culture-derived myofibroblasts in injured rabbit medial collateral ligaments (MCL) and in intact anterior cruciate ligaments (ACL)....

The discovery of the myofibroblast has opened new perspectives for the comprehension of the biological mechanisms involved in wound healing and fibrotic diseases. In recent years, many advances have been made in understanding important aspects of myofibroblast basic biological characteristics. This review summarizes such advances in several fields,...

The arterial adventitia has been long considered an essentially supportive tissue; however, more and more data suggest that it plays a major role in the modulation of the vascular tone by complex interactions with structures located within intima and media. The purpose of this review is to summarize these data and to describe the mechanisms involve...

The aim of our study was to advance the knowledge about the biological differences in the healing of the anterior cruciate ligament (ACL) versus the medial collateral ligament (MCL). We quantified α-smooth muscle actin (α-SMA) expression and TGF-β receptor I (TGF-βRI) expression in experimentally injured rabbit ligaments (from day 3 to 12 weeks pos...

The discovery of the myofibroblast (Gabbiani et al., Experientia 27:549–550, 1971; Tomasek et al., Nat Rev Mol Cell Biol 3:349–363, 2002) has opened a new perspective in the understanding of phenomena such as connective tissue remodeling and epithelial–mesenchymal interactions that play crucial roles in normal and pathological processes including...

The benefit of drug-eluting stents (DES) is the remarkable reduction in the rates of both restenosis and target lesion revascularization. However, the risk of thrombotic complications extends further in DES-implanted arteries compared with those treated with bare-metal stents (BMS). Moreover, in-stent thrombosis (IST) and delayed arterial healing i...

Kidney diseases are a major source of morbidity and mortality in humans. In developed countries, mortality owing to chronic kidney disease (CKD) terminating in end-stage renal failure is comparable with that associated with cancer. A full understanding of the mechanisms implicated in the progression of CKD is needed to achieve its prevention and to...

The crucial role of the myofibroblast in wound healing and fibrosis development is well established. This review discusses the mechanisms of myofibroblast action and the new findings that may develop into therapeutic strategies during the next few years.

Myofibroblast-induced remodeling of collagenous extracellular matrix is a key component of our body's strategy to rapidly and efficiently repair damaged tissues; thus myofibroblast activity is considered crucial in assuring the mechanical integrity of vital organs and tissues after injury. Typical examples of beneficial myofibroblast activities are...

Epithelial-to-mesenchymal transition (EMT) is involved in embryonic development as well as in several pathological conditions. Literature indicates that polyamine availability may affect transcription of c-myc, matrix metalloproteinase (MMP)1, MMP2, TGFbeta(1), and collagen type I mRNA. The aim of this study was to elucidate polyamines role in EMT...

Using newly generated monoclonal antibodies, we have compared the distribution of beta- and gamma-cytoplasmic actin in fibroblastic and epithelial cells, in which they play crucial roles during various key cellular processes. Whereas beta-actin is preferentially localized in stress fibers, circular bundles and at cell-cell contacts, suggesting a ro...

In the adult heart, cardiac muscle comprises the working myocardium and the conduction system (CS). The latter includes the sinoatrial node (SAN), the internodal tract or bundle (IB), the atrioventricular node (AVN), the atrioventricular bundle (AVB), the bundle branches (BB) and the peripheral Purkinje fibers (PF). Most of the information concerni...

In a rat model of long-lasting pressure-overload hypertrophy, we investigated whether changes in the relative expression of myocardial actin isoforms are among the early signs of ventricular mechanical dysfunction before the transition toward decompensation. Forty-four rats with infrarenal aortic banding (AC rats) were studied. Hemodynamic paramete...

Normal wound healing includes a number of overlapping phases. After injury, there is an early inflammatory step characterised by haemorrhage and clotting. At this time, the wound has a provisional serum-derived extracellular matrix, which serves to seal the wound temporarily and allows the invasion of cells that carry out the repair process. In the...

The Discoglossus pictus egg has a specific site of sperm-egg interaction, the dimple, which has a well-defined cytoskeleton. We studied whether there are cytoskeletal and cytoskeleton-related proteins typically involved in the polarization of plasma membrane proteins. The identity and the localization of the molecules cross-reacting with antispectr...

When compared to age-matched control aponeurosis, lesions of Dupuytren's disease contain higher contents of water, collagen and chondroitin-sulphate, as well as increased proportions of soluble collagen and of reducible cross-links; these indicate synthesis of new collagen. The lesions show also increased amounts of type III collagen and an increas...

The presence in insect tracheal taenidia of a protein having an immunochemical determinant common to vertebrate keratins is suggested. Taenidia react positively with a specific anti keratin serum both at the fluorescent and electron microscope level. In tracheal preparations, immunoblotting shows specificity for three polypeptides having molecular...

We studied the effects of cytostatic drugs on porcine coronary artery spindle-shaped (S) and rhomboid (R) smooth muscle cell (SMC) biological activities related to intimal thickening (IT) formation. Imatinib, and to a lesser extent curcumin, decreased proliferation of S- and R-SMCs and migratory and urokinase activities of R-SMCs more efficiently c...

The endoplasmic reticulum (ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains uncle...

To investigate the modulation of cellular retinol-binding protein (CRBP)-1 and the desmosomal plaque proteins plakophilin (PKP)-1 and desmoplakin (DP) in correlation with the Ki67+ proliferation index (PI) during the progression of cervical squamous intraepithelial lesions (SIL) to squamous cell carcinoma (SCC). Using in situ imaging by brightfield...

The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver f...

We reported that smooth muscle cell (SMC) populations isolated from normal porcine coronary artery media exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). R-SMCs are recovered in higher proportion from stent-induced intimal thickening compared with media suggesting that they participate in intimal thickening formation. Our aim was t...

Mechanisms that regulate host defense to noninfectious tissue injury are poorly understood. Here we summarize our recent work investigating the role of the innate immune response in regulating the inflammatory and fibrotic response to noninfectious lung injury. We have identified key roles for two cell surface receptors in regulating lung inflammat...

Hepatic stellate cells are perisinusoidal fibroblasts that transdifferentiate into myofibroblasts in response to paracrine factors released from cancer cells and cancer-activated endothelial cells. Tumor-associated myofibroblasts exhibit contractility, proliferation, production of extracellular matrix molecules and metalloproteases. They secrete so...

Most of the present knowledge on the pathomechanism of renal fibrosis is based on experimental studies with laboratory animals. Today, a variety of genetic and inducible animal models that mimic primary causes of human disease, such as diabetes mellitus, glomerulonephritis or lupus erythematodes are available. However, only few of these models prog...

Fibroblasts are a heterogeneous population of structural cells whose primary function is the production of extracellular matrix for normal tissue maintenance and repair. However, fibroblasts provide much more than structural support as they synthesize and respond to many different cytokines and lipid mediators and are intimately involved in the pro...

Peritoneal dialysis (PD) is an alternative to hemodialysis for the treatment of end-stage renal disease and is based on the use of the peritoneum as a semi-permeable membrane for water and solutes. Peritoneal membrane fibrosis (or sclerosis) is one of the most frequent complications of PD that includes a wide spectrum of peritoneal structural chang...

Asthma is characterized by functional and structural alterations of the bronchial epithelium, chronic airway inflammation and remodeling of the normal bronchial architecture. Bronchial myofibroblasts are thought to play a crucial role in the pathogenesis of subepithelial fibrosis, a prominent aspect of the remodeling process. The results of the stu...

Cancer cell invasion necessitates the participation of host cells. One of the cell types that stimulates invasion of colon and other cancer cells is the myofibroblast, as evidenced from the histology of cancer and from coculture experiments. Cancer cells produce transforming growth factor-β (TGF-β) and TGF-β converts fibroblasts into pro-invasive m...

The role of myofibroblasts in various fibrotic disorders is currently well established. These smooth-muscle-like fibroblasts promote deposition of ECM proteins and contractility of lung parenchyma. The present studies were performed to characterize the contractile activity of SSc lung fibroblasts. Previously, we demonstrated that the early stages o...

Mechanical forces are central to the control of 3D spatial organisation in connective tissue remodelling, repair and scarring. How this operates is increasingly seen as the next major research focus in this area. In contrast to mechanics at the tissue-scale, cell-level mechanics (or cytomechanics) is dominated by the cell-matrix-material interplay....

Epidemiological and autopsy studies suggest a close link between aging and the clinical manifestation of atherosclerosis. Several experiments show increased arterial susceptibility to atherogenetic stimuli in aged subjects. All together, these findings support the concept that aging represents an independent atherogenetic risk factor, intimately as...

Oxidized low-density lipoprotein (LDL) is associated with cardiovascular disease. Macrophages contribute to LDL oxidation, and oxidized LDL (oxLDL) affects macrophage function. We searched for the strongest gene correlates of oxLDL in macrophages in coronary plaques and studied the effect of oxLDL on their expression in THP-1 cells. Gene expression...

It is well known that arterial smooth muscle cells (SMC) of adult rats, cultured in a medium containing fetal calf serum (FCS), replicate actively and lose the expression of differentiation markers, such as desmin, smooth muscle (SM) myosin and alpha-SM actin. We report here that compared to freshly isolated cells, primary cultures of SMC from newb...

Cellular retinol binding protein-1 (CRBP-1) contributes to the maintenance of the differentiative state of endometrial glandular cells through the regulation of bioavailability of retinol and derivatives, but its role in endometrial oncogenetic process remains unclear. Antibodies to CRBP-1, estrogen and progesterone receptors (ER and PR) were appli...

The origin of myxoma, the most frequent tumour of the heart, remains uncertain. Previous phenotypic characterizations have shown heterogeneous results and the most recent hypothesis suggests that cardiac myxoma originates from a primitive pluripotential cardiogenic cell. We investigated the expression of actin isoforms in 30 left atrial myxomas by...

We have analysed alterations of alpha-skeletal actin expression and volume fraction of fibrosis in the ventricular myocardium and their functional counterpart in terms of arrhythmogenesis and haemodynamic variables, in rats with different degrees of compensated cardiac hypertrophy induced by infra-renal abdominal aortic coarctation. The following c...

During wound healing and fibrocontractive diseases fibroblasts acquire a smooth muscle cell-like phenotype by differentiating into contractile force generating myofibroblasts. We examined whether regulation of myofibroblast contraction in granulation tissue is dominated by Ca2+-induced phosphorylation of myosin light chain kinase or by Rho/Rho kina...

See related article, pages 472–479 The concept that the atheromatous plaque undergoes a complex inflammatory and fibroproliferative process, which is likely responsible for the onset of complications,1 and the notion of vulnerable plaque2 have acquired wide acceptance during the last years. The crucial participation in these events of inflammator...

Characterize the phenotypic features of media and intima coronary artery smooth muscle cells (SMCs) in mildly stenotic plaques, erosions, stable plaques, and in-stent restenosis. Expression of alpha-smooth muscle actin (alpha-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin was investigated by immunohistochemistry followed by morpho...

The recognition of the role of the myofibroblast in granulation tissue contraction and connective tissue remodeling during fibrocontractive diseases has allowed a theoretical and practical progress in the understanding of these pathologies. The observation that TGF-β is the key cytokine in myofibroblast differentiation, correlated with its role in...

Phenotypic modulation of vascular smooth muscle cells (SMCs) in atherosclerosis and restenosis involves responses to the surrounding microenvironment. SMCs obtained by enzymatic digestion from tunica media of newborn, young adult (YA) and old rats and from the thickened intima (TI) and underlying media of young adult rat aortas 15 days after balloo...

Lung myofibroblasts play a major role in the pathophysiology of asthma, contributing not only to tissue remodelling but also to airway inflammation. Nevertheless, only recently, attention has been focused on these cells as potential targets for anti-allergic drugs. Herein, we analysed the pharmacological response of lung myofibroblasts to beta2-ago...

We have previously shown that the N-terminal sequence AcEEED of alpha-smooth-muscle actin causes the loss of alpha-smooth-muscle actin from stress fibers and a decrease in cell contractility when introduced in myofibroblasts as a cell-penetrating fusion peptide. Here, we have investigated the function of this sequence on stress fiber organization i...

Synemin, a very unique type VI intermediate filament (IF) protein, exhibits alternative splice variants termed a and b. Unlike other IF proteins, synemin binds to actin-associated proteins, including a-actinin, vinculin, and a-dystrobrevin. Our previous work has demonstrated the presence of synemin in differentiating astrocytes. In this study, we h...

Synemin, a very unique type VI intermediate filament (IF) protein, exhibits alternative splice variants termed alpha and beta. Unlike other IF proteins, synemin binds to actin-associated proteins, including alpha-actinin, vinculin, and alpha-dystrobrevin. Our previous work has demonstrated the presence of synemin in differentiating astrocytes. In t...

We describe a new animal model designed to assess the impact of ischemia on wound healing. Eight patterns of arterial lesion in the limb were first tested in 24 Wistar rats. Resection of the external iliac artery down to the femoral artery at the level of the knee was chosen as the reference model and performed on the left limb of 45 rats; the righ...

Proliferation and migration of smooth muscle cells (SMCs) from the media towards the intima are key events in atherosclerosis and restenosis. During these processes, SMC undergo phenotypic modulations leading to SMC dedifferentiation. The identification and characterization of factors controlling these phenotypic changes are crucial in order to pre...

We have compared the distribution of β‐ and γ‐cytoplasmic actins in highly motile cells using laser confocal microscopy and newly developed β‐ and γ‐cytoplasmic actins monoclonal antibodies as well as the commercially available β‐actin antibody (clone Ac74). When fibroblastic, epithelial or endothelial cells attach on a substrate, divide, move into...

Objectives: Characterize the phenotypic features of smooth muscle cells (SMCs) of erosions, stable plaques and in stent restenosis causing sudden death, in order to verify the possibility that they have modulated into myofibroblasts. Methods and Results: Expression of α-SM actin (α-SMA), SM myosin heavy chains (SMMHCs) and smoothelin was investigat...

The main differences between the six known actin isoforms are located in their amino terminus, suggesting a crucial importance for this region in terms of actin isoform function and organization. We have recently supported this assumption by demonstrating that the α-smooth muscle actin N-terminal sequence AcEEED introduced in myofibroblasts as a ce...

After the first description of the myofibroblast in granulation tissue of an open wound by means of electron microscopy, as an intermediate cell between the fibroblast and the smooth muscle cell, the myofibroblast has been identified both in normal tissues, particularly in locations where there is a necessity of mechanical force development, and in...

Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiated state of the endometrium through retinol bioavailability regulation. The aim was to analyse CRBP-1 expression in endometrial stromal cells at eutopic and ectopic sites in different physiopathological conditions. Antibodies to CRBP-1, CD10 and alpha-smoo...

Modulation of actin isoform expression is a well-established feature of developmental phenomena. As one might expect, it is also characteristic of several pathological situations that are the subject of the present review. alpha-Smooth muscle actin has proven to be a reliable marker for identifying (a) vascular smooth muscle cells during vascular d...

Wound healing and fibrocontractive diseases are characterized by the presence of a cell called myofibroblast that is responsible for pathological tissue remodeling. TGF-beta is the main stimulus for the fibrolast/myofibroblast modulation. Alpha-smooth muscle (SM) actin, the actin isoform typical of vascular smooth muscle cells, is the main marker o...

Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability...

Primary aldosteronism causes severe hypertension in humans (Conn's syndrome) with cardiac hypertrophy, characterized by a fibrosis more severe than the one observed in patients with essential hypertension. This suggests that aldosterone by itself may have specific and direct effects on cardiac remodeling through the activation of the cardiac minera...