A model for positive feedback control of the transformation of fibroblasts to myofibroblasts

Elson, Elliot L.; Qian, Hong; Fee, Judy A.; Wakatsuki, Toshiyuki

doi:10.1016/j.pbiomolbio.2018.08.004

Cited by 22 publications

(22 citation statements)

References 41 publications

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“…For example, fibroblasts can convert to protomyofibroblasts, which have actin stress fibers, enhanced collagen expression, and extra domain A (EDA)-fibronectin expression, but they do not express α-SMA. 136 Plateletderived growth factor is one factor that has been shown to initiate the conversion of fibroblasts to protomyofibroblasts 137 ; active TGF-β is then necessary to convert protomyofibroblasts to myofibroblasts. 68,136 In addition, as indicated with the "matrifibrocyte" experiments above, a myofibroblast could downregulate α-SMA expression while still maintaining elevated collagen secretion.…”

Section: Activated Fibroblasts and Myofibroblastsmentioning

confidence: 99%

Mechanisms of cardiac collagen deposition in experimental models and human disease

Cowling

Kupsky

Kahn

et al. 2019

Translational Research

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The inappropriate deposition of extracellular matrix within the heart (termed cardiac fibrosis) is associated with nearly all types of heart disease, including ischemic, hypertensive, diabetic, and valvular. This alteration in the composition of the myocardium can physically limit cardiomyocyte contractility and relaxation, impede electrical conductivity, and hamper regional nutrient diffusion. Fibrosis can be grossly divided into 2 types, namely reparative (where collagen deposition replaces damaged myocardium) and reactive (where typically diffuse collagen deposition occurs without myocardial damage). Despite the widespread association of fibrosis with heart disease and general understanding of its negative impact on heart physiology, it is still not clear when collagen deposition becomes pathologic and translates into disease symptoms. In this review, we have summarized the current knowledge of cardiac fibrosis in human patients and experimental animal models, discussing the mechanisms that have been deduced from the latter in relation to the former. Because assessment of the extent of fibrosis is paramount both as a research tool to further understanding and as a clinical tool to assess patients, we have also summarized the current state of noninvasive/minimally invasive detection systems for cardiac fibrosis. Albeit not exhaustive, our aim is to provide an overview of the current understanding of cardiac fibrosis, both clinically and experimentally.

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Section: Activated Fibroblasts and Myofibroblastsmentioning

confidence: 99%

Mechanisms of cardiac collagen deposition in experimental models and human disease

Cowling

Kupsky

Kahn

et al. 2019

Translational Research

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“…The mechanisms underlying the effects of both ketotifen and ranitidine on the expression of α-smooth muscle actin, vimentin, and desmin should be investigated in later study. Furthermore, the cells isolated from intact skin were also positive for α-smooth muscle actin, vimentin, and desmin; hence, it is possible that the skin fibroblasts were transformed into myofibroblasts when in contact with the stiff seeding substrate [20].…”

Section: Discussionmentioning

confidence: 99%

Histamine augments collagen content via H1 receptor stimulation in cultures of myofibroblasts taken from wound granulation tissue

et al. 2020

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The inflammatory reaction influences the deposition of collagen within wound granulation tissue. The aim of the present study is to determine whether histamine acting directly on myofibroblasts derived from wound granulation tissue may influence collagen deposition. It also identifies the histamine receptor involved in this process. The experiments were carried out on cells isolated from the granulation tissue of a wound model (a polypropylene net inserted subcutaneously to rats) or intact rat skin. Collagen content was measured following the addition of different concentrations of histamine and treatment with histamine receptor antagonists (ketotifen – H1 inhibitor, ranitidine – H2 inhibitor) and a histamine receptor H1 agonist (2-pyridylethylamine dihydrochloride).The cells were identified as myofibroblasts: alpha-smooth muscle actin, vimentin, and desmin positive in all experimental conditions. Histamine increased the collagen level within both cell cultures, i.e., those isolated from granulation tissue or intact skin. It did not, however, influence the expression of either the collagen type I or III genes within the cultured myofibroblasts. Histamine activity was reduced by ketotifen (the H1 receptor inhibitor) and increased by the H1 receptor agonist, as demonstrated by changes in the levels of collagen in the myofibroblast culture. Histamine increased collagen content within the cultures, acting directly on myofibroblasts via H1 receptor stimulation.

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“…Moreover, the increased deposition of highly cross-linked extracellular matrix (ECM) represents a significant physical barrier to the delivery of therapeutical agents to the affected tissue. As mentioned in the previous section, clinical intervention is further complicated by the self-sustaining nature of myofibroblasts that, by secreting profibrotic cytokines and generating tensile force, produce a local environment permissive to the persistence and propagation of fibrosis [2].…”

Section: Background and Rationale Of The Studymentioning

confidence: 99%

“…Profibrotic mechanical signals are transduced both directly via the Rho cascade (due to the physical continuity of cytoskeletal and ECM components at FA sites) and indirectly via the release of latent TGF-β1 stores from the ECM [25,26]. It is important to highlight that, by secreting TGF-β1 and generating high levels of mechanical tension, myofibroblasts produce both of the "master regulators" that promote their own generation and survival; this positive feedback loop sustains their dysregulated persistence and activity, contributing to the well-documented difficulty of the clinical treatment of fibrosis [2].…”

Section: Outline Of Myofibroblast Biology and Ontologymentioning

confidence: 99%

Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

Siani

2020

SN Compr. Clin. Med.

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The term “fibrosis” refers to a spectrum of connective tissue disorders characterized by the excessive accumulation of extracellular matrix leading to organ dysfunction and, ultimately, failure. Fibrosis affects millions of patients worldwide and often manifests itself as a late-stage pathological condition associated with poor prognostic outcome. Although the aetiology and clinical course vary widely depending on the affected organ, fibrotic degeneration of different tissues is underpinned by similar molecular and cellular mechanisms, most notably the persistence and dysregulated activity of myofibroblasts. A systematic search of clinical trials was conducted using PubMed and Cochrane to qualitatively evaluate the effectiveness of different therapeutic approaches to the pharmacological targeting of myofibroblasts in patients affected by fibrotic disorders. The systematic search and screening returned 54 eligible clinical trials, 38 of which reported an improvement of the patients’ symptoms following treatment. The majority of the eligible articles focused on fibrotic degeneration of the respiratory system, skin, liver, and kidneys. The evaluation of clinical data unearthed commonalities between strategies that successfully ameliorated symptoms in patients affected by the same fibrotic disorder. However, none of the treatments evaluated in this study could improve symptoms across a range of fibrotic pathologies. These results indicate that, although no “one size fits all” treatment for fibrosis has yet been identified, the systematic analysis of clinical data can be used to inform the development of therapeutical strategies tailored to suit the diverse aetiology of each fibrotic condition.

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A model for positive feedback control of the transformation of fibroblasts to myofibroblasts

Cited by 22 publications

References 41 publications

Mechanisms of cardiac collagen deposition in experimental models and human disease

Mechanisms of cardiac collagen deposition in experimental models and human disease

Histamine augments collagen content via H1 receptor stimulation in cultures of myofibroblasts taken from wound granulation tissue

Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

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