Differential Behaviors of Atrial Versus Ventricular Fibroblasts A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
TL;DR: Atrial fibroblasts behave differently than ventricular fibro Blasts over a range of in vitro and in vivo paradigms, with atrial Fibroblast showing enhanced reactivity that may explain greater atrial fibrotic responses.
Abstract: Background— In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined. Methods and Results— We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater α-smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([3H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β1. Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congesti...
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TL;DR: Lai et al. as discussed by the authors showed that TGF-β1 promoted endothelial-mesenchymal transition during atrial fibrillation and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources.
Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.
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TL;DR: The reprogramming strategy as an alternative to current cellular-based approaches to myocardial regeneration is discussed, raising the exciting possibility that human cardiac fibroblasts may be amenable to treatments designed to alter cellular identity in vivo.
Abstract: The hearts of lower vertebrates have remarkable regenerative capacity.1 Neonatal mouse hearts are also capable of repairing damaged myocardium; however, this capacity is lost barely 2 weeks after birth.2 The human adult myocardium is replenished throughout life,3 and studies suggest that this occurs as a result of division of existing cardiomyocytes,4 with a possible contribution from resident adult cardiac stem cells.5,6 Combined, these findings raise the prospect that it may be possible to activate the endogenous regenerative reserve of the heart to restore function in failing hearts.
Complementing this approach, new genetic reprogramming technologies, based on the pioneering work by the 2012 Physiology and Medicine Nobel laureates Gurdon7 and Yamanaka,8 have shown promise for the repair of myocardial damage. In this context, 4 recent articles9–12 demonstrated that differentiated adult fibroblasts can be genetically reprogrammed into cardiomyocyte-like cells, termed induced cardiomyocytes (iCMs), raising the possibility that direct genetic reprogramming may have therapeutic applications. Given that fibroblasts constitute ≈40% of cells within the adult heart, if efficient conversion rates could be achieved, this may yield the billions of cardiomyocytes required to replenish the heart after an ischemic event. Crucially, the reprogramming process occurs in postmyocardial infarct heart,10,11 as well as the laboratory dish. This finding raises the exciting possibility that human cardiac fibroblasts may be amenable to treatments designed to alter cellular identity in vivo. In this commentary, we discuss the reprogramming strategy as an alternative to current cellular-based approaches to myocardial regeneration (Figure).
Figure.
A genetic reprogramming strategy as a potential alternative to cell-based attempts at myocardial regeneration. A , Potential issues with cell administration to regenerate cardiac function include modest efficacy, poor engraftment, potential for tumor formation, and poor electric integration of injected cells. B …
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Cites background from "Differential Behaviors of Atrial Ve..."
...For example, it is now apparent that not all cardiac fibroblasts are the same, with atrial fibroblasts having enhanced reactivity and a greater fibrotic response than ventricular fibroblasts.(67) A reprogramming therapy targeted to ventricular fibroblasts might be expected to affect systolic function and avoid potential adverse effects on atrial fibroblasts....
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TL;DR: It is demonstrated for the first time that TRPC1 activation by ET-1 is mediated by protein kinase C through the distinct phospholipids pathways phosphoinositide-3-kinase and phospholIPase C and that the TR PC1 channel and ETA receptor are upregulated in AF atria, which are likely involved in atrial electrical remodeling in patients with AF.
3 citations
TL;DR: Clinical parameters and histological findings are examined to clarify the factors involved in LAAT formation and to help clarify the role of EMTs in this process.
Abstract: Although recent echocardiographic studies have suggested that left atrial appendage (LAA) remodeling contributes to the development of LAA thrombus (LAAT), histological evidence is absent. The objective of this study was to examine clinical parameters and histological findings to clarify the factors involved in LAAT formation.
3 citations
TL;DR: It is revealed that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources, and offer possibilities for therapeutic targeting of fibrosis in AF.
Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.
3 citations
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TL;DR: It is shown that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart.
Abstract: Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
1,908 citations
TL;DR: Experimental CHF strongly promotes the induction of sustained AF by causing interstitial fibrosis that interferes with local conduction, with important potential implications for understanding, treating, and preventing AF related to CHF.
Abstract: Background—Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which “AF begets AF” but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm). Methods and Results—CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8±4 seconds in control dogs to 535±82 seconds; P<0.01), similar to the effect of 1 week of RAP (713±300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in th...
1,343 citations
TL;DR: Cultured fetal and adult human fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibro Blasts.
Abstract: A fundamental feature of the architecture and functional design of vertebrate animals is a stroma, composed of extracellular matrix and mesenchymal cells, which provides a structural scaffold and conduit for blood and lymphatic vessels, nerves, and leukocytes. Reciprocal interactions between mesenchymal and epithelial cells are known to play a critical role in orchestrating the development and morphogenesis of tissues and organs, but the roles played by specific stromal cells in controlling the design and function of tissues remain poorly understood. The principal cells of stromal tissue are called fibroblasts, a catch-all designation that belies their diversity. We characterized genome-wide patterns of gene expression in cultured fetal and adult human fibroblasts derived from skin at different anatomical sites. Fibroblasts from each site displayed distinct and characteristic transcriptional patterns, suggesting that fibroblasts at different locations in the body should be considered distinct differentiated cell types. Notable groups of differentially expressed genes included some implicated in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways that control proliferation, cell migration, and fate determination. Several genes implicated in genetic diseases were found to be expressed in fibroblasts in an anatomic pattern that paralleled the phenotypic defects. Finally, adult fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibroblasts.
1,055 citations
TL;DR: The two PDGF null phenotypes reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis, and show that PDGF-B is required in the ontogeny of kidney mesangial cells.
854 citations
TL;DR: TGF-beta induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF- beta, is decreased by down-regulation of PDGF receptor alpha subunits and perhaps by direct growth inhibition.
760 citations