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Circulation Research Jul 2020Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although... (Review)
Review
Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although myofibroblast formation is a physiological response to acute injury, such as myocardial infarction, myofibroblast persistence, as occurs in heart failure, contributes to maladaptive remodeling and progressive functional decline. Although traditional pathways of activation, such as TGFβ (transforming growth factor β) and AngII (angiotensin II), have been well characterized, less understood are the alterations in mitochondrial function and cellular metabolism that are necessary to initiate and sustain myofibroblast formation and function. In this review, we highlight recent reports detailing the mitochondrial and metabolic mechanisms that contribute to myofibroblast differentiation, persistence, and function with the hope of identifying novel therapeutic targets to treat, and potentially reverse, tissue organ fibrosis.
Topics: Animals; Calcium Signaling; Cell Differentiation; Energy Metabolism; Fibrosis; Heart Diseases; Humans; Mitochondria, Heart; Myofibroblasts
PubMed: 32673537
DOI: 10.1161/CIRCRESAHA.120.316958 -
Nature Reviews. Rheumatology Jan 2020Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for... (Review)
Review
Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.
Topics: Animals; Apoptosis; Extracellular Matrix; Fibrosis; Humans; Myofibroblasts; Scleroderma, Systemic
PubMed: 31792399
DOI: 10.1038/s41584-019-0324-5 -
Experimental Eye Research Jan 2016Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and... (Review)
Review
Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.
Topics: Actins; Cell Differentiation; Collagen; Eye Injuries; Fibroblasts; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Myofibroblasts; Wound Healing
PubMed: 26192991
DOI: 10.1016/j.exer.2015.07.009 -
Cold Spring Harbor Perspectives in... Jan 2023Myofibroblasts are the construction workers of wound healing and repair damaged tissues by producing and organizing collagen/extracellular matrix (ECM) into scar tissue.... (Review)
Review
Myofibroblasts are the construction workers of wound healing and repair damaged tissues by producing and organizing collagen/extracellular matrix (ECM) into scar tissue. Scar tissue effectively and quickly restores the mechanical integrity of lost tissue architecture but comes at the price of lost tissue functionality. Fibrotic diseases caused by excessive or persistent myofibroblast activity can lead to organ failure. This review defines myofibroblast terminology, phenotypic characteristics, and functions. We will focus on the central role of the cell, ECM, and tissue mechanics in regulating tissue repair by controlling myofibroblast action. Additionally, we will discuss how therapies based on mechanical intervention potentially ameliorate wound healing outcomes. Although myofibroblast physiology and pathology affect all organs, we will emphasize cutaneous wound healing and hypertrophic scarring as paradigms for normal tissue repair versus fibrosis. A central message of this review is that myofibroblasts can be activated from multiple cell sources, varying with local environment and type of injury, to either restore tissue integrity and organ function or create an inappropriate mechanical environment.
Topics: Humans; Myofibroblasts; Cicatrix; Wound Healing; Collagen; Fibrosis; Extracellular Matrix; Cell Differentiation
PubMed: 36123034
DOI: 10.1101/cshperspect.a041231 -
American Journal of Respiratory Cell... Jan 2021Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also...
Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 (transforming growth factor-β1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-β1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.
Topics: Animals; Cells, Cultured; Histones; Humans; Indoles; Lactates; Lung; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Myofibroblasts; Pulmonary Fibrosis; Pyridones
PubMed: 33074715
DOI: 10.1165/rcmb.2020-0360OC -
Current Opinion in Rheumatology Jan 2013Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins... (Review)
Review
PURPOSE OF REVIEW
Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins and the mechanisms underpinning their differentiation and/or transition. The objective of the review is to highlight this recent progress.
RECENT FINDINGS
The epithelial origin of the myofibroblast in fibrosis has been challenged by recent studies, with the pericyte suggested as a possible precursor instead. Additional signaling pathways, including Notch, Wnt, and hedgehog, are implicated in myofibroblast differentiation. The importance of NADPH oxidase 4 was highlighted recently to suggest a potential link between cellular/oxidative stress and the genesis of the myofibroblast. Recent observations on the importance of lysophosphatidic acid in fibrosis suggest that this may be due, in part, to its ability to regulate myofibroblast differentiation. Finally, there is increasing evidence for the role of epigenetic mechanisms in regulating myofibroblast differentiation, including DNA methylation and miRNA regulation of gene expression.
SUMMARY
These recent discoveries open up a whole new array of potential targets for novel antifibrotic therapies. This is of special importance given the current bleak outlook for chronic progressive fibrotic diseases, such as scleroderma, due to lack of effective therapies.
Topics: Cell Differentiation; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Myofibroblasts; Signal Transduction
PubMed: 23114586
DOI: 10.1097/BOR.0b013e32835b1352 -
Chest Dec 2019Airway remodeling is a characteristic feature of asthma and is thought to play an important role in the pathogenesis of airway hyperresponsiveness. Myofibroblasts are... (Review)
Review
Airway remodeling is a characteristic feature of asthma and is thought to play an important role in the pathogenesis of airway hyperresponsiveness. Myofibroblasts are key structural cells involved in injury and repair, and there is evidence that dysregulation of their normal function contributes to airway remodeling. Despite the importance of myofibroblasts, a lack of specific cellular markers and inconsistent nomenclature have limited recognition of their key role in airway remodeling. Myofibroblasts are increased several-fold in the airways in asthma, in proportion to the severity of the disease. Myofibroblasts are postulated to be derived from both tissue-resident and bone marrow-derived cells, depending on the stage of injury and the tissue. A small number of studies have demonstrated attenuation of myofibroblast numbers and also reversal of established myofibroblast populations in asthma and other inflammatory processes. In this article, we review what is currently known about the biology of myofibroblasts in the airways in asthma and identify potential targets to reduce or reverse the remodeling process. However, further translational research is required to better understand the mechanistic role of the myofibroblast in asthma.
Topics: Airway Remodeling; Animals; Asthma; Humans; Myofibroblasts
PubMed: 31472157
DOI: 10.1016/j.chest.2019.08.1917 -
Inflammation Research : Official... Mar 2019Myofibroblasts, specialized fibroblasts expressing the protein alpha-smooth muscle actin, are instrumental in wound contraction during normal wound healing. Tissue... (Review)
Review
Myofibroblasts, specialized fibroblasts expressing the protein alpha-smooth muscle actin, are instrumental in wound contraction during normal wound healing. Tissue shortening is then stabilized by the synthesis of extracellular matrix, collagen in particular. Alpha-smooth muscle actin within myofibroblasts becomes organized in filamentous bundles, called stress fibers, that allow the retractile movement producing wound contraction. During hypertrophic scarring, skin deformations depend on the inappropriate action of these stress fibers that for unknown reasons persist even after the epithelialization of the wound. This historical review article is dedicated to the reconstruction of the discovery of this cell by the Italian scientist Giulio Gabbiani.
Topics: Cell Biology; History, 20th Century; History, 21st Century; Myofibroblasts
PubMed: 30610292
DOI: 10.1007/s00011-018-01211-x -
Particle and Fibre Toxicology Nov 2016Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production... (Review)
Review
Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production of CNT materials may increase the risk of human exposure to CNTs. Studies in rodents have shown that certain forms of CNTs are potent fibrogenic inducers in the lungs to cause interstitial, bronchial, and pleural fibrosis characterized by the excessive deposition of collagen fibers and the scarring of involved tissues. The cellular and molecular basis underlying the fibrotic response to CNT exposure remains poorly understood. Myofibroblasts are a major type of effector cells in organ fibrosis that secrete copious amounts of extracellular matrix proteins and signaling molecules to drive fibrosis. Myofibroblasts also mediate the mechano-regulation of fibrotic matrix remodeling via contraction of their stress fibers. Recent studies reveal that exposure to CNTs induces the differentiation of myofibroblasts from fibroblasts in vitro and stimulates pulmonary accumulation and activation of myofibroblasts in vivo. Moreover, mechanistic analyses provide insights into the molecular underpinnings of myofibroblast differentiation and function induced by CNTs in the lungs.In view of the apparent fibrogenic activity of CNTs and the emerging role of myofibroblasts in the development of organ fibrosis, we discuss recent findings on CNT-induced lung fibrosis with emphasis on the role of myofibroblasts in the pathologic development of lung fibrosis. Particular attention is given to the formation and activation of myofibroblasts upon CNT exposure and the possible mechanisms by which CNTs regulate the function and dynamics of myofibroblasts in the lungs. It is evident that a fundamental understanding of the myofibroblast and its function and regulation in lung fibrosis will have a major influence on the future research on the pulmonary response to nano exposure, particle and fiber-induced pneumoconiosis, and other human lung fibrosing diseases.
Topics: Animals; Humans; Myofibroblasts; Nanotubes, Carbon; Pulmonary Fibrosis
PubMed: 27814727
DOI: 10.1186/s12989-016-0172-2 -
Oral Diseases Mar 2018In oral cancer, acquisition of α-smooth muscle actin (α-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important... (Review)
Review
In oral cancer, acquisition of α-smooth muscle actin (α-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important event for progression and metastasis. However, the contribution of myofibroblasts in oral potentially malignant disorders (OPMD) remains controversial. This systematic review provides evidence that immunodetection of myofibroblasts may identify oral submucous fibrosis (OSMF) with high risk of malignant transformation, but does not represent an auxiliary tool to predict the malignant potential of leukoplakia and erythroplakia, the most common OPMD.
Topics: Actins; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Humans; Mouth Neoplasms; Myofibroblasts; Oral Submucous Fibrosis; Precancerous Conditions
PubMed: 29480603
DOI: 10.1111/odi.12694