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Signal Transduction and Targeted Therapy Jun 2022Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop... (Review)
Review
Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.
Topics: Endothelial Cells; Fibroblasts; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Liver Cirrhosis; Myofibroblasts
PubMed: 35773269
DOI: 10.1038/s41392-022-01070-3 -
Experimental Eye Research Aug 2020The corneal wound healing response is typically initiated by injuries to the epithelium and/or endothelium that may also involve the stroma. However, it can also be... (Review)
Review
The corneal wound healing response is typically initiated by injuries to the epithelium and/or endothelium that may also involve the stroma. However, it can also be triggered by immune or infectious processes that enter the stroma via the limbal blood vessels. For mild injuries or infections, such as epithelial abrasions or mild controlled microbial infections, limited keratocyte apoptosis occurs and the epithelium or endothelium regenerates, the epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) is repaired, and keratocyte- or fibrocyte-derived myofibroblast precursors either undergo apoptosis or revert to the parent cell types. For more severe injuries with extensive damage to EBM and/or DBM, delayed regeneration of the basement membranes leads to ongoing penetration of the pro-fibrotic cytokines transforming growth factor (TGF) β1, TGFβ2 and platelet-derived growth factor (PDGF) that drive the development of mature alpha-smooth muscle actin (SMA)+ myofibroblasts that secrete large amounts of disordered extracellular matrix (ECM) components to produce scarring stromal fibrosis. Fibrosis is dynamic with ongoing mitosis and development of SMA + myofibroblasts and continued autocrine-or paracrine interleukin (IL)-1-mediated apoptosis of myofibroblasts and their precursors. Eventual repair of the EBM and/or DBM can lead to at least partial resolution of scarring fibrosis.
Topics: Animals; Apoptosis; Cornea; Corneal Injuries; Extracellular Matrix; Humans; Myofibroblasts; Regeneration; Wound Healing
PubMed: 32553485
DOI: 10.1016/j.exer.2020.108089 -
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 -
Advanced Drug Delivery Reviews Jun 2021Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into... (Review)
Review
Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) "off-target" small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and "pleiotropic" drug delivery systems.
Topics: Animals; Drug Delivery Systems; Extracellular Matrix; Fibrosis; Humans; Myocardium; Myofibroblasts; Pharmaceutical Preparations
PubMed: 33831476
DOI: 10.1016/j.addr.2021.03.021 -
Cells Apr 2022The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to... (Review)
Review
The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to maladaptive fibrotic remodeling. Following myocardial infarction, cardiac fibroblasts undergo dynamic phenotypic transitions, contributing to the regulation of inflammatory, reparative, and angiogenic responses. This review manuscript discusses the mechanisms of regulation, roles and fate of fibroblasts in the infarcted heart. During the inflammatory phase of infarct healing, the release of alarmins by necrotic cells promotes a pro-inflammatory and matrix-degrading fibroblast phenotype that may contribute to leukocyte recruitment. The clearance of dead cells and matrix debris from the infarct stimulates anti-inflammatory pathways and activates transforming growth factor (TGF)-β cascades, resulting in the conversion of fibroblasts to α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Activated myofibroblasts secrete large amounts of matrix proteins and form a collagen-based scar that protects the infarcted ventricle from catastrophic complications, such as cardiac rupture. Moreover, infarct fibroblasts may also contribute to cardiac repair by stimulating angiogenesis. During scar maturation, fibroblasts disassemble α-SMA+ stress fibers and convert to specialized cells that may serve in scar maintenance. The prolonged activation of fibroblasts and myofibroblasts in the infarct border zone and in the remote remodeling myocardium may contribute to adverse remodeling and to the pathogenesis of heart failure. In addition to their phenotypic plasticity, fibroblasts exhibit remarkable heterogeneity. Subsets with distinct phenotypic profiles may be responsible for the wide range of functions of fibroblast populations in infarcted and remodeling hearts.
Topics: Animals; Cicatrix; Fibroblasts; Mammals; Myocardial Infarction; Myocardium; Myofibroblasts; Transforming Growth Factor beta
PubMed: 35563692
DOI: 10.3390/cells11091386 -
British Journal of Haematology Oct 2020Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR... (Review)
Review
Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK-STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro-inflammatory cytokines (IL-1 ß, TGF-ß), growth factors (b-FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation-enhanced (MIPSS 70-plus version 2.0) and genetically-inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for risk-adapted therapeutic decisions. A major challenge remains the dearth of disease-modifying drugs, whereas allogeneic transplant offers the chance of long-term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.
Topics: Gene Expression Regulation; Humans; Mutation; Myofibroblasts; Primary Myelofibrosis
PubMed: 32196650
DOI: 10.1111/bjh.16576 -
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 -
The European Respiratory Journal Dec 2022Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to...
BACKGROUND
Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development; however, the role of BMP4 in modulating lung fibrosis remains unknown.
METHODS
The aim of this study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts and lung samples from patients with IPF.
RESULTS
BMP4 expression was downregulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with transforming growth factor (TGF)-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. BMP4 overexpression using adeno-associated virus 9 vectors showed preventative and therapeutic efficacy against lung fibrosis. , BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Pink1 silencing by short-hairpin RNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signalling and suppression of TGF-β1-mediated Smad2/3 signalling and .
CONCLUSION
Strategies for enhancing BMP4 signalling may represent an effective treatment for pulmonary fibrosis.
Topics: Animals; Mice; Bleomycin; Bone Morphogenetic Protein 4; Cellular Senescence; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Mice, Inbred C57BL; Mitophagy; Myofibroblasts; Protein Kinases; Transforming Growth Factor beta1
PubMed: 35777761
DOI: 10.1183/13993003.02307-2021 -
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 -
Frontiers in Immunology 2022Renal fibrosis causes structural and functional impairment of the kidney, which is a dominant component of chronic kidney disease. Recently, a novel mechanism,... (Review)
Review
Renal fibrosis causes structural and functional impairment of the kidney, which is a dominant component of chronic kidney disease. Recently, a novel mechanism, macrophage-to-myofibroblast transition (MMT), has been identified as a crucial component in renal fibrosis as a response to chronic inflammation. It is a process by which bone marrow-derived macrophages differentiate into myofibroblasts during renal injury and promote renal fibrosis. Here, we summarized recent evidence and mechanisms of MMT in renal fibrosis. Understanding this phenomenon and its underlying signal pathway would be beneficial to find therapeutic targets for renal fibrosis in chronic kidney disease.
Topics: Fibrosis; Humans; Kidney; Macrophages; Myofibroblasts; Renal Insufficiency, Chronic
PubMed: 35990655
DOI: 10.3389/fimmu.2022.934377