50 Years of Myofibroblasts: How the Myofibroblast Concept Evolved.

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 in smooth muscle. The contractile function of myofibroblasts was demonstrated by measuring the contraction of strips of granulation tissue in response to smooth muscle agonists and in cell culture.

Fascia Is Able to Actively Contract and May Thereby Influence Musculoskeletal Dynamics: A Histochemical and Mechanographic Investigation.

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 from different body sites were investigated for the presence of myofibroblasts using immunohistochemical staining for α-smooth muscle actin ( 31 donors, 20 animals).

Sudden coronary death in the young: Evidence of contractile phenotype of smooth muscle cells in the culprit atherosclerotic plaque.

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).

Monoclonal antibodies against muscle actin isoforms: epitope identification and analysis of isoform expression by immunoblot and immunostaining in normal and regenerating skeletal muscle.

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, are due to 3-4 amino acid differences located in their acetylated N-decapeptide sequence. The first monoclonal antibody (mAb) against an actin isoform (α-SMA) was produced and characterized in our laboratory in 1986 (Skalli  et al.

The myofibroblast in wound healing and fibrosis: answered and unanswered questions.

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 lesion.

Stable incorporation of α-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms.

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 addressed the molecular mechanism by which α-SMA is stably incorporated into stress fibers in human myofibroblasts following exposure to TGFβ1.

The prehistory of the cytoskeleton concept.

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.

HANS SELYE: AN INSPIRING TEACHER.

The present writing is a recollection of Hans Selye, as an educator of graduate and post-graduate students. His main aim in teaching his students was to encourage originality and significance of all scientific research.

Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β.

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 numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown.

Smooth muscle cells of human intracranial aneurysms assume phenotypic features similar to those of the atherosclerotic plaque.

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 smoothelin in 26 sIAs and 15 nonaneurysmal cerebral arteries. In addition, S100A4, a recently identified marker of dedifferentiated SMCs in atherosclerotic plaques, was also investigated.

Altered collagen expression in jugular veins in multiple sclerosis.

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 veins (IJVs), we have studied the morphological and biological features of IJVs in MS patients.

Methods: We examined (a) IJVs specimens from MS patients who underwent surgical reconstruction of the IJV and specimens of the great saphenous vein used for surgical reconstruction, (b) different vein specimens from an MS patient dead of an unrelated cause, and (c) autoptical and surgical IJV specimens from patients without MS.

Resveratrol treatment reduces cardiac progenitor cell dysfunction and prevents morpho-functional ventricular remodeling in type-1 diabetic rats.

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 protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.

Epithelial-mesenchymal crosstalk alteration in kidney fibrosis.

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 this refined pharmacological approach has failed to stop progression to end-stage renal disease (ESRD) in many individuals. In vitro historical data and recent new findings have suggested that progression of renal fibrosis might occur as a result of an altered tubulo-interstitial microenvironment and, more specifically, as a result of an altered epithelial-mesenchymal crosstalk.

The role of the myofibroblast in tumor stroma remodeling.

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 myofibroblasts in the stroma reaction to epithelial tumors is well established and many data are accumulating which suggest that the stroma compartment is an active participant in tumor onset and/or evolution. In this review we summarize the evidence in favor of this concept, the main mechanisms that regulate myofibroblast differentiation and function, as well as the biophysical and biochemical factors possibly involved in epithelial-stroma interactions, using liver carcinoma as main model, in view of achieving a better understanding of tumor progression mechanisms and of tools directed toward stroma as eventual therapeutic target.

Autologous transplantation of culture-born myofibroblasts into intact and injured rabbit ligaments.

Purpose: 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).

Methods: Fibroblasts isolated from the iliotibial band were cultured in the presence of transforming growth factor beta-1 (TGF-β1) for five days and analysed for α-SMA expression.

Transient expression of cellular retinol-binding protein-1 during cardiac repair after myocardial infarction.

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.

Recent developments in myofibroblast biology: paradigms for connective tissue remodeling.

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, such as the following: i) force production by the myofibroblast and mechanisms of connective tissue remodeling; ii) factors controlling the expression of α-smooth muscle actin, the most used marker of myofibroblastic phenotype and, more important, involved in force generation by the myofibroblast; and iii) factors affecting genesis of the myofibroblast and its differentiation from precursor cells, in particular epigenetic factors, such as DNA methylation, microRNAs, and histone modification.

Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology.

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 involved in adventitia/media and adventitia/intima cross-talk. In response to a plethora of stimuli, the adventitia undergoes remodeling processes, resulting in positive (adaptive) remodeling, negative (constrictive) remodeling, or both.

Renal fibrosis and proteomics: current knowledge and still key open questions for proteomic investigation.

Renal tubulo-interstitial fibrosis is a non-specific process, representing the final common pathway for all kidney diseases, irrespective of their initial cause, histological injury, or etiology, leading to gradual expansion of the fibrotic mass which destroys the normal structure of the tissue and results in organ dysfunction and, ultimately, in end-stage organ failure. Proteomic studies of the fibrotic pathophysiological mechanisms have been performed in cell cultures, animal models and human tissues, addressing some of the key issues. This article will review proteomic contribution to the raising current knowledge on renal fibrosis biology and also mention seminal open questions to which proteomic techniques and proteomists could fruitfully contribute.

Drug-eluting stent: importance of clinico-pathological correlations.

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 in DES-treated arteries have been identified by histological examination.

Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives.

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.

The kidney as a target organ in pharmaceutical research.

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 delay the need for support strategies based on dialysis and transplantation.

α-Smooth muscle actin and TGF-β receptor I expression in the healing rabbit medial collateral and anterior cruciate ligaments.

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 post-injury). Myofibroblasts (α-SMA positive cells) were identified as early as the third day post-injury in MCL and their density increased steadily up to day 21.