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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 -
Archives of Pathology & Laboratory... Oct 2018Liposarcoma is divided into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. Dedifferentiated liposarcoma displays the greatest histomorphologic... (Review)
Review
CONTEXT.—
Liposarcoma is divided into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. Dedifferentiated liposarcoma displays the greatest histomorphologic diversity, including a subset with myofibroblastic differentiation that shares similarities with a spectrum of reactive, benign, and malignant soft tissue lesions. Misdiagnosis may lead to deleterious consequences, as dedifferentiated liposarcoma differs significantly in its prognosis and treatment from its mimics.
OBJECTIVE.—
To review the clinicopathologic, immunohistochemical, and molecular features of the myofibroblastic variant of dedifferentiated liposarcoma as well as the key distinguishing features from its mimics.
DATA SOURCES.—
Review of pertinent literature on major features and current understanding of dedifferentiated liposarcoma with myofibroblastic differentiation.
CONCLUSIONS.—
The myofibroblastic variant of dedifferentiated liposarcoma is an uncommon and underrecognized sarcoma with several important differential diagnoses, and likely represents the major subset of aggressive retroperitoneal tumors that may have been misdiagnosed as desmoid-type fibromatosis, inflammatory myofibroblastic tumor, or another type of sarcoma in the past.
Topics: Humans; Liposarcoma; Myofibroblasts
PubMed: 30281365
DOI: 10.5858/arpa.2018-0205-RA -
Biochemical and Biophysical Research... Jul 2021Fibrosis is a condition characterized by the overproduction of extracellular matrix (ECM) components (e.g., collagen) in the myofibroblasts, causing tissue hardening and...
Fibrosis is a condition characterized by the overproduction of extracellular matrix (ECM) components (e.g., collagen) in the myofibroblasts, causing tissue hardening and eventual organ dysfunction. Currently, the molecular mechanisms that regulate ECM production in the myofibroblasts are still obscure. In this study, we investigated the function of GPRC5B in the cardiac and lung myofibroblasts using real-time RT-PCR and siRNA-mediated knockdown. We discovered a significantly high expression of Gprc5b in the tissues of the fibrosis mice models and confirmed that Gprc5b was consistently expressed in the myofibroblasts of fibrotic hearts and lungs. We also found that Gprc5b expression was associated and may be dependent on the actin-MRTF-SRF signaling pathway. Notably, we observed that Gprc5b knockdown reduced the expression of collagen genes in the cardiac and lung myofibroblasts. Therefore, our findings reveal that GPRC5B enhances collagen production in the myofibroblasts, which directly promotes fibrosis in the tissues.
Topics: Animals; Collagen; Disease Models, Animal; Extracellular Matrix; Fibrosis; Heart; Liver; Lung; Male; Mice; Myofibroblasts; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34023784
DOI: 10.1016/j.bbrc.2021.05.035 -
Advanced Drug Delivery Reviews Nov 2017Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also... (Review)
Review
Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of myofibroblasts in tumor progression, invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor progression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will then discuss the state-of-the art drug targeting technologies to myofibroblasts in context of the above-mentioned organs and tumor microenvironment. The overall objective of this review is therefore to advance our understanding in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for designing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer.
Topics: Animals; Antineoplastic Agents; Fibrosis; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Myofibroblasts; Neoplasms
PubMed: 28720422
DOI: 10.1016/j.addr.2017.07.010 -
The Tohoku Journal of Experimental... Jun 2013Fibrosis is a state, in which excess amounts of extracellular matrix are deposited in the tissue. Fibrosis can occur in various organs, including the liver, lung, kidney... (Review)
Review
Fibrosis is a state, in which excess amounts of extracellular matrix are deposited in the tissue. Fibrosis can occur in various organs, including the liver, lung, kidney and heart. The progression of fibrosis involves interstitial hypercellularity, accumulation of extracellular matrix, and atrophy of epithelial structures, resulting in a loss of normal function. Myofibroblasts play a crucial role in the development and progress of fibrosis. When stimulated, myofibroblasts actively synthesize connective tissue components and cause organ fibrosis. As a result, the process and the mechanism of myofibroblast activation represent a target for antifibrotic treatment. As yet, however, an effective treatment has not been developed, and new treatment modalities are expected. Because activation of myofibroblasts is a key event during fibrosis development, there is great interest in identifying and characterizing proteins whose expression is changed after this activation. In this review, fibrosis is outlined and the role of myofibroblasts in this disorder is described. Furthermore, the search for candidate proteins to target for treatment and the prospects of antifibrotic therapy are discussed.
Topics: Animals; Extracellular Matrix; Fibrosis; Humans; Kidney Diseases; Lung Diseases, Interstitial; Myofibroblasts; Proteome; Proteomics; Sclerosis; Signal Transduction; Transforming Growth Factor beta
PubMed: 23774326
DOI: 10.1620/tjem.230.67 -
Journal of Molecular and Cellular... Nov 2022Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into...
BACKGROUND
Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation.
METHODS
Stable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1) on myofibroblast formation in both murine and human cardiac fibroblasts. We employed immunofluorescence staining, functional gel contraction, western blotting, and bioenergetic assays to determine the myofibroblast phenotype.
RESULTS
Carbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFβ-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart.
CONCLUSIONS
These results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.
Topics: Humans; Mice; Animals; Myofibroblasts; Glutamine; Fibroblasts; Collagen; Cells, Cultured
PubMed: 35988357
DOI: 10.1016/j.yjmcc.2022.08.002 -
Ear, Nose, & Throat Journal Sep 2021
Topics: Adolescent; Child; Female; Head and Neck Neoplasms; Humans; Male; Medical Illustration; Myofibroblasts; Neoplasms, Muscle Tissue; Young Adult
PubMed: 31760795
DOI: 10.1177/0145561319890165 -
Cellular and Molecular Life Sciences :... Nov 2018Bronchial asthma is a chronic inflammatory disease in which bronchial wall remodelling plays a significant role. This phenomenon is related to enhanced proliferation of... (Review)
Review
Bronchial asthma is a chronic inflammatory disease in which bronchial wall remodelling plays a significant role. This phenomenon is related to enhanced proliferation of airway smooth muscle cells, elevated extracellular matrix protein secretion and an increased number of myofibroblasts. Phenotypic fibroblast-to-myofibroblast transition represents one of the primary mechanisms by which myofibroblasts arise in fibrotic lung tissue. Fibroblast-to-myofibroblast transition requires a combination of several types of factors, the most important of which are divided into humoural and mechanical factors, as well as certain extracellular matrix proteins. Despite intensive research on the nature of this process, its underlying mechanisms during bronchial airway wall remodelling in asthma are not yet fully clarified. This review focuses on what is known about the nature of fibroblast-to-myofibroblast transition in asthma. We aim to consider possible mechanisms and conditions that may play an important role in fibroblast-to-myofibroblast transition but have not yet been discussed in this context. Recent studies have shown that some inherent and previously undescribed features of fibroblasts can also play a significant role in fibroblast-to-myofibroblast transition. Differences observed between asthmatic and non-asthmatic bronchial fibroblasts (e.g., response to transforming growth factor β, cell shape, elasticity, and protein expression profile) may have a crucial influence on this phenomenon. An accurate understanding and recognition of all factors affecting fibroblast-to-myofibroblast transition might provide an opportunity to discover efficient methods of counteracting this phenomenon.
Topics: Airway Remodeling; Asthma; Bronchi; Cell Differentiation; Cell Shape; Fibroblasts; Fibrosis; Humans; Myofibroblasts
PubMed: 30101406
DOI: 10.1007/s00018-018-2899-4 -
The Journal of Experimental Medicine Sep 2021Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1)...
Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
Topics: Adult; Aged; Animals; Case-Control Studies; Cell Differentiation; Cytoskeleton; Female; Gene Expression Regulation; Homeodomain Proteins; Humans; Male; Mice, Knockout; Middle Aged; Myofibroblasts; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Young Adult; rho-Associated Kinases; Mice
PubMed: 34259830
DOI: 10.1084/jem.20201916 -
Cells Jul 2021Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved... (Review)
Review
Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell? We will here take the position of a fibrosis researcher (which, coincidentally, we are) to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses.
Topics: Fibroblasts; Foreign-Body Reaction; Humans; Macrophages; Mechanotransduction, Cellular; Myofibroblasts; Prostheses and Implants
PubMed: 34359963
DOI: 10.3390/cells10071794