Cardiac Fibroblasts in Cell Culture Systems: Myofibroblasts All Along?

Rohr, Stephan

doi:10.1097/fjc.0b013e3182137e17

Cited by 68 publications

(60 citation statements)

References 95 publications

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“…Very few markers are unique to fibroblasts, and often none of these markers are constantly expressed by cardiac fibroblasts. Often an activated fibroblast is referred to as a myofibroblast with the predominant molecular markers being SMA and vimentin (Santiago et al, 2010;Rohr, 2011). These, of course, are also expressed by other mesenchymal cells, including VSMC.…”

Section: Discussionmentioning

confidence: 99%

The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors

et al. 2012

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SUMMARYThe basic helix-loop-helix (bHLH) family of transcription factors orchestrates cell-fate specification, commitment and differentiation in multiple cell lineages during development. Here, we describe the role of a bHLH transcription factor, Tcf21 (epicardin/Pod1/capsulin), in specification of the cardiac fibroblast lineage. In the developing heart, the epicardium constitutes the primary source of progenitor cells that form two cell lineages: coronary vascular smooth muscle cells (cVSMCs) and cardiac fibroblasts. Currently, there is a debate regarding whether the specification of these lineages occurs early in the formation of the epicardium or later after the cells have entered the myocardium. Lineage tracing using a tamoxifen-inducible Cre expressed from the Tcf21 locus demonstrated that the majority of Tcf21-expressing epicardial cells are committed to the cardiac fibroblast lineage prior to initiation of epicardial epithelial-to-mesenchymal transition (EMT). Furthermore, Tcf21 null hearts fail to form cardiac fibroblasts, and lineage tracing of the null cells showed their inability to undergo EMT. This is the first report of a transcription factor essential for the development of cardiac fibroblasts. We demonstrate a unique role for Tcf21 in multipotent epicardial progenitors, prior to the process of EMT that is essential for cardiac fibroblast development.

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Section: Discussionmentioning

confidence: 99%

The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors

et al. 2012

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“…At the end of development, cardiac fibroblasts surround and run parallel to myocytes throughout the myocardium, and are generally maintained in a quiescent state; they produce ECM proteins and matrix metalloproteinases (MMPs) in a tightly regulated balance to maintain homeostasis (Porter and Turner, 2009). stiffness and composition can also promote CM hypertrophy (Ieda et al, 2009). Finally, the release of profibrotic factors, such as TGF-β1, AngII and FGF by CFs have all been shown to promote CM hypertrophy (Rohr, 2011), leading to thickening of the muscular walls that are then able to generate stronger contractions and enhance mechanotransductive signaling throughout the heart. These tissue-level forces are transmitted to the different cardiac cells through the cardiac ECM and through intercellular adhesions between them.…”

Section: Cardiac Cell Responses To Mechanical Stressmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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“…155,156 Cardiac fibroblasts grown under standard culture conditions undergo a phenotypic switch to myofibroblasts because of the mechanical tension of the rigid substrate. 157,158 In one way this may preclude functional differences between the two types of fibroblasts if the intention is to study one specific phenotype. On the other hand, these cultures contain fibroblasts at different stages of myofibroblast differentiation, similar to what is observed in the pressure-overloaded heart in vivo.…”

Section: Primary Cardiac Cell Culturesmentioning

confidence: 99%

“…On the other hand, these cultures contain fibroblasts at different stages of myofibroblast differentiation, similar to what is observed in the pressure-overloaded heart in vivo. 157,159 Although neonatal cardiac cell cultures have shortcomings as model systems for the adult heart, they provide a controlled environment to study direct effects of physical or biochemical interventions on a specific cell type and are highly valued in cardiac research. In light of this, we used the primary cell cultures to investigate whether the matrix molecules we found to be upregulated in the diseased heart may act in an auto-or paracrine fashion to convey signaling effects on cardiac cells.…”

Section: Primary Cardiac Cell Culturesmentioning

confidence: 99%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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Cardiac Fibroblasts in Cell Culture Systems: Myofibroblasts All Along?

Cited by 68 publications

References 95 publications

The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors

The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

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