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Cardiac Fibroblast Physiology and Pathology

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ABSTRACT

Cardiac function is mediated by interactions between the cellular constituents of the heart, as well as the extracellular matrix. The major cell types of the heart include cardiac fibroblasts, myocytes, endothelial cells, and vascular smooth muscle cells. In addition, there are also resident stem cells and transient cell types, such as immune cells. Interactions in the heart include chemical, mechanical, and electrical signals, which vary depending on the developmental stage, disease state, and specific cell type. Understanding how these different signals interact at the molecular, cellular, and organ levels is important for better understanding cardiac function under a variety of physiological and pathological conditions. Cardiac fibroblasts play key roles in maintaining normal cardiac form and function, as well as in the cardiac remodeling process during pathological conditions, such as myocardial infarction and hypertension. Regardless of normal or pathological status of the heart, fibroblasts have multiple functions, such as synthesis and deposition of extracellular matrix and cell‐cell communication with other cardiac cells, including myocytes and endothelial cells. Interactions with other cell types can affect multiple cell signaling pathways (e.g., ERK, JNK, and p38), the expression and secretion of numerous growth factors and cytokines, microRNA exchange, gene and protein expression, and angiogenesis. In this review, we provide insight into the cardiac fibroblast under normal and pathological conditions to illustrate their importance in maintaining proper cardiac function. © 2015 American Physiological Society. Compr Physiol 5:887‐909, 2015.

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Figure 1. Figure 1. Dynamic interactions in the heart and fibroblast function. (A) The cells in the heart can communicate through multiple channels, including chemical, mechanical, and electrical signaling. Chemical signals can include growth factors, cytokines, and hormones that can act in an autocrine or paracrine fashion. Mechanical signals include changes in contraction, stretch, and pressure. Electrical signals involve the opening and closing of ion channels, as well as the connexins. It is the dynamic interactions between these signals that allows for proper form and function of the heart. Disruption of any of these signals leads to disruption of the other signal types and ultimately leads to cardiac failure. In addition, there is interplay between these chemical, electrical, and mechanical signals and ECM synthesis, degradation, and composition, which also plays a role in cardiac function. (B) The cardiac fibroblast acts as a sentinel cell and responds to a wide range of stimuli. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell‐cell communication with myocytes, cell‐cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors, and cytokines, as well as potentiating blood vessel formation.
Figure 2. Figure 2. The cardiac fibroblast. Cardiac fibroblasts are the main cellular constituent in the heart. (A) Fibroblasts are morphologically recognizable by their shape, abundant rough endoplasmic reticulum and prominent nucleoli when active. (B) Confocal microscopy image of cardiac fibroblasts in culture. Cultures have been stained with vimentin (red), a fibroblast marker. (C) Confocal micrograph of a section of the left ventricle of a mouse heart stained with vimentin (red), phalloidin (green), and DAPI (blue). Notice the cardiac fibroblasts interweaving between the cardiac myocytes in the heart. (D) Electron micrograph of a section of the left ventricle of a mouse heart. Scale bars are defined as the following: (B) scale bar = 50 μm, (C) scale bar = 25 μm, and (D) scale bar = 2 μm.
Figure 3. Figure 3. Myofibroblasts express smooth muscle cell markers. Cardiac myofibroblasts express the smooth muscle marker, α‐smooth muscle actin. Confocal micrographs of isolated murine cardiac fibroblasts treated with TGF‐β (5 ng/mL) for 24 h to induce the myofibroblast phenotype. Cardiac fibroblasts were stained with (A) DAPI (blue), (B) α‐smooth muscle actin (yellow), and (C) vimentin (red). Overlay of the three panels is shown in D.
Figure 4. Figure 4. Sources of fibroblasts and myofibroblasts. Myofibroblasts can originate from a variety of sources and exhibit both adaptive as well as maladaptive effects in the pressure‐overloaded and/or injured myocardium. Cardiac myofibroblasts can be derived from the cardiac epithelium and endothelium via mesenchymal transition (EndMT and EMT), as well as from perivascular cells, circulating monocytes and bone marrow‐derived progenitors, particularly in the inured or stressed myocardium. Resident cardiac fibroblasts also contribute to this pool by undergoing proliferation stimulated by mechanical stress or locally produced factors such as angiotensin II (Ang II). Expression of α‐smooth muscle actin (α‐SMA) identifies differentiated myofibroblasts in the stressed or injured myocardium. During the early stages of the fibrotic response, myofibroblasts lack α‐SMA expression and are termed proto‐myofibroblasts, which ultimately differentiate into myofibroblasts; however, recent studies suggest that these cells may also express α‐SMA. The presence of Ang II, growth factors and mechanical stretch are stimulators of this process. The resultant myofibroblasts remodel the architecture of the myocardium through the production of matrix proteins, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases. The cardiac myofibroblasts also become a “secretome,” which produces Ang II and a variety of fibrogenic growth factors such as fibroblast growth factor (FGF) and transforming growth factor‐β, which in turn act to stimulate transformation of proto‐myofibroblasts to myofibroblasts and production of collagen I and, therefore, fibrosis.
Figure 5. Figure 5. Organization and interactions of cells in the heart. Myocytes, fibroblasts, and endothelial cells can interact though various cell surface molecules, through gap junctions in either a homotypic or a heterotypic fashion, and via growth factors, cytokines, and hormones that can act in both a paracrine and autocrine manner. These various interactions among cardiac cell types can cause the activation or silencing of different cell signaling pathways and lead to changes in gene and protein expression.
Figure 6. Figure 6. Integrin‐linked activation of stress‐activated protein kinases in cardiac fibroblasts. The effects of extracellular matrix on cardiac fibroblast function are primarily mediated through integrins. Integrins couple to a variety of signal transduction pathways through the activation of Talin, Src, Kindlin‐2, and integrin‐linked kinase (ILK). Two of the major cascade systems activated by integrins are the stress‐activated protein kinases, JNK and p38, which play an important role in the migration and growth of cardiac fibroblasts that occur during cardiac fibrosis.
Figure 7. Figure 7. AT1 receptor signaling in cardiac fibroblasts. The AT1 receptor (AT1R) couples to signaling pathways through G‐protein dependent and G‐protein‐independent pathways. Activation of G‐protein‐dependent signaling has been associated with the activation of growth‐related pathways in cardiac fibroblasts. The activation of AT1R by angiotensin II binding results in G‐protein‐dependent activation of phospholipase C, subsequent release of calcium from calcium stores, in addition to PKC activation and downstream activation of the ERK signaling cascade. The AT1R can also be activated by mechanical stretch, in which G‐protein independent signaling through the scaffolding protein β‐arrestin‐2, which couples to activation of the JNK signaling cascade that has been associated with cell migration. The C‐terminus of activated AT1R contains a docking site for a nonreceptor tyrosine kinase, Janus kinase 2 (JAK2), SHP‐2, and a protein tyrosine kinase (PTK), such as Fyn. Interaction with activated AT1R stimulates JAK2 autophosphorylation/activation, followed by JAK2‐dependent dimerization of signal tranducer and activator of transcription (STAT) proteins, their translocation to the nucleus and induction of early growth response genes associated with growth.
Figure 8. Figure 8. Mechanosensing in cardiac fibroblasts. Mechanical stretch is transduced through a variety of mechanoreceptors, which includes integrins, the angiotensin type 1 receptor (AT1R), stretch‐activated channels (SACs), and potentially discoidin domain receptor 2 (DDR2). Much of the mechanotransduction is orchestrated through activation of the Rho GTPases, Rac1, and RhoA. Kinases and adaptor proteins at focal adhesion complexes, such as Talin, Src, Kindlin‐2, integrin‐linked kinase (ILK), paxillin, and vinculin also aid in maintaining intracellular structure against extracellular matrix (ECM) forces through remodeling of the actin cytoskeleton. Mechanical signaling influences downstream signaling pathways involving stress‐activated protein kinases (JNK and p38) and survival/growth‐mediated pathways, such as Akt, which further regulate and modify cardiac fibroblast function to meet the demands of the extracellular environment.
Figure 9. Figure 9. Effects of IL‐1 on cardiac fibroblast signaling and function. Activation of the IL‐1 receptor in cardiac fibroblasts results in activation of MAPK signaling cascades (ERK, JNK, and p38) and NFκB, which modulate the expression of specific genes in cardiac fibroblasts that promote angiogenesis, inflammation, and cell migration, as well a degradation of the ECM.
Figure 10. Figure 10. The circulating and local cardiac renin angiotensin system. Angiotensin II (Ang II), the biologically active product of the renin‐angiotensin system (RAS,) has been demonstrated to play an important role in heart failure and cardiac hypertrophy. Classically, the RAS has been viewed as an endocrine system, in which the liver, kidney, and lung have participated in the production of Ang II through the production of angiotensinogen, rennin, and angiotensin converting enzyme (ACE), respectively. This view has been modified since several components of the RAS are now known to be produced by several peripheral tissues, including the heart. Both cardiac myocytes and fibroblasts have been demonstrated to generate all components of the RAS, as well as additional factors, such as tonin and chymase. This circulating RAS appears to be most important for overall vascular tone and salt and water balance, whereas the local cardiac RAS is thought to be important for regulating both physiologic and pathologic function in the heart. In cardiac fibroblasts, activation of the AT1 receptor has been demonstrated to stimulate cardiac remodeling via inducing gene expression of collagen, MMPs, TIMPs, cytokines, growth factors, as well as positive feedback for increased production of RAS components.
Figure 11. Figure 11. Effects of IL‐6 on cardiac fibroblast signaling and function. Activation of the IL‐6 cell surface receptor in cardiac fibroblasts leads to activation of associated Janus kinases (JAK), and in turn tyrosine phosphorylation of the receptors, and recruitment and tyrosine phosphorylation of signal transducer and activator of transcription (STAT) molecules. Different protein tyrosine phosphatases, such as SHP‐1can attenuate JAK activation by dephosphorylation. SHP‐1 associates through their SH2 domains with the IL‐6 receptor and can modulate JAK activation. Tyrosine phosphorylated STATs form dimers, which are capable of translocation to the nucleus, by reciprocal interaction of the (C‐terminally located) SH2 domains with the phosphotyrosine motifs. After translocation into the nucleus, the STAT dimers interact with the gamma interferon activation site (GAS) elements to induce target gene transcription associated with cardiac remodeling. Nuclear dephosphorylation of STATs by protein tyrosine phosphatases (PTPs) controls the amplitude and duration of STAT signaling. The dephosphorylated STAT molecules then become available for a new cycle of activation.
Figure 12. Figure 12. Cell communication in the heart. Cardiac fibroblasts and myocytes interact with both the extracellular matrix (ECM) and other cell types in the heart. Integrins and DDR2 are major receptor systems which interact with the ECM and couple to intracellular signaling pathways that regulate cellular function. Cardiac cell types can also interact through cell surface receptors, such as cadherins or more directly through gap junctions. Cell‐cell communication between cell types can take place through gap junctions, which are comprised of one or more types of connexins, allows for the exchange of ions and small molecules (e.g., small signaling proteins and/or microRNAs) between adjoining cells.
Figure 13. Figure 13. microRNA interplay between cells in the heart. Cell‐cell communication is important for proper development and maintaining normal cardiac function. Recent studies have demonstrated that miRNAs play a key role in cellular communication and in regulating gene expression and cellular functions. miRNAs can be trafficked multiple ways, in an intracellular or extracellular manner. Intracellular miRNA can have its effect on the host cell after being processed from pre‐miRNA to mature‐miRNA or it can be passed to an adjacent cell through tight gap junctions and have its effect on the adjacent cell. Extracellular miRNA can move into the bloodstream and have an effect on endothelial cells or distant cells and tissues. It can also be secreted into the ECM and be taken up by another cell.


Figure 1. Dynamic interactions in the heart and fibroblast function. (A) The cells in the heart can communicate through multiple channels, including chemical, mechanical, and electrical signaling. Chemical signals can include growth factors, cytokines, and hormones that can act in an autocrine or paracrine fashion. Mechanical signals include changes in contraction, stretch, and pressure. Electrical signals involve the opening and closing of ion channels, as well as the connexins. It is the dynamic interactions between these signals that allows for proper form and function of the heart. Disruption of any of these signals leads to disruption of the other signal types and ultimately leads to cardiac failure. In addition, there is interplay between these chemical, electrical, and mechanical signals and ECM synthesis, degradation, and composition, which also plays a role in cardiac function. (B) The cardiac fibroblast acts as a sentinel cell and responds to a wide range of stimuli. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell‐cell communication with myocytes, cell‐cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors, and cytokines, as well as potentiating blood vessel formation.


Figure 2. The cardiac fibroblast. Cardiac fibroblasts are the main cellular constituent in the heart. (A) Fibroblasts are morphologically recognizable by their shape, abundant rough endoplasmic reticulum and prominent nucleoli when active. (B) Confocal microscopy image of cardiac fibroblasts in culture. Cultures have been stained with vimentin (red), a fibroblast marker. (C) Confocal micrograph of a section of the left ventricle of a mouse heart stained with vimentin (red), phalloidin (green), and DAPI (blue). Notice the cardiac fibroblasts interweaving between the cardiac myocytes in the heart. (D) Electron micrograph of a section of the left ventricle of a mouse heart. Scale bars are defined as the following: (B) scale bar = 50 μm, (C) scale bar = 25 μm, and (D) scale bar = 2 μm.


Figure 3. Myofibroblasts express smooth muscle cell markers. Cardiac myofibroblasts express the smooth muscle marker, α‐smooth muscle actin. Confocal micrographs of isolated murine cardiac fibroblasts treated with TGF‐β (5 ng/mL) for 24 h to induce the myofibroblast phenotype. Cardiac fibroblasts were stained with (A) DAPI (blue), (B) α‐smooth muscle actin (yellow), and (C) vimentin (red). Overlay of the three panels is shown in D.


Figure 4. Sources of fibroblasts and myofibroblasts. Myofibroblasts can originate from a variety of sources and exhibit both adaptive as well as maladaptive effects in the pressure‐overloaded and/or injured myocardium. Cardiac myofibroblasts can be derived from the cardiac epithelium and endothelium via mesenchymal transition (EndMT and EMT), as well as from perivascular cells, circulating monocytes and bone marrow‐derived progenitors, particularly in the inured or stressed myocardium. Resident cardiac fibroblasts also contribute to this pool by undergoing proliferation stimulated by mechanical stress or locally produced factors such as angiotensin II (Ang II). Expression of α‐smooth muscle actin (α‐SMA) identifies differentiated myofibroblasts in the stressed or injured myocardium. During the early stages of the fibrotic response, myofibroblasts lack α‐SMA expression and are termed proto‐myofibroblasts, which ultimately differentiate into myofibroblasts; however, recent studies suggest that these cells may also express α‐SMA. The presence of Ang II, growth factors and mechanical stretch are stimulators of this process. The resultant myofibroblasts remodel the architecture of the myocardium through the production of matrix proteins, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases. The cardiac myofibroblasts also become a “secretome,” which produces Ang II and a variety of fibrogenic growth factors such as fibroblast growth factor (FGF) and transforming growth factor‐β, which in turn act to stimulate transformation of proto‐myofibroblasts to myofibroblasts and production of collagen I and, therefore, fibrosis.


Figure 5. Organization and interactions of cells in the heart. Myocytes, fibroblasts, and endothelial cells can interact though various cell surface molecules, through gap junctions in either a homotypic or a heterotypic fashion, and via growth factors, cytokines, and hormones that can act in both a paracrine and autocrine manner. These various interactions among cardiac cell types can cause the activation or silencing of different cell signaling pathways and lead to changes in gene and protein expression.


Figure 6. Integrin‐linked activation of stress‐activated protein kinases in cardiac fibroblasts. The effects of extracellular matrix on cardiac fibroblast function are primarily mediated through integrins. Integrins couple to a variety of signal transduction pathways through the activation of Talin, Src, Kindlin‐2, and integrin‐linked kinase (ILK). Two of the major cascade systems activated by integrins are the stress‐activated protein kinases, JNK and p38, which play an important role in the migration and growth of cardiac fibroblasts that occur during cardiac fibrosis.


Figure 7. AT1 receptor signaling in cardiac fibroblasts. The AT1 receptor (AT1R) couples to signaling pathways through G‐protein dependent and G‐protein‐independent pathways. Activation of G‐protein‐dependent signaling has been associated with the activation of growth‐related pathways in cardiac fibroblasts. The activation of AT1R by angiotensin II binding results in G‐protein‐dependent activation of phospholipase C, subsequent release of calcium from calcium stores, in addition to PKC activation and downstream activation of the ERK signaling cascade. The AT1R can also be activated by mechanical stretch, in which G‐protein independent signaling through the scaffolding protein β‐arrestin‐2, which couples to activation of the JNK signaling cascade that has been associated with cell migration. The C‐terminus of activated AT1R contains a docking site for a nonreceptor tyrosine kinase, Janus kinase 2 (JAK2), SHP‐2, and a protein tyrosine kinase (PTK), such as Fyn. Interaction with activated AT1R stimulates JAK2 autophosphorylation/activation, followed by JAK2‐dependent dimerization of signal tranducer and activator of transcription (STAT) proteins, their translocation to the nucleus and induction of early growth response genes associated with growth.


Figure 8. Mechanosensing in cardiac fibroblasts. Mechanical stretch is transduced through a variety of mechanoreceptors, which includes integrins, the angiotensin type 1 receptor (AT1R), stretch‐activated channels (SACs), and potentially discoidin domain receptor 2 (DDR2). Much of the mechanotransduction is orchestrated through activation of the Rho GTPases, Rac1, and RhoA. Kinases and adaptor proteins at focal adhesion complexes, such as Talin, Src, Kindlin‐2, integrin‐linked kinase (ILK), paxillin, and vinculin also aid in maintaining intracellular structure against extracellular matrix (ECM) forces through remodeling of the actin cytoskeleton. Mechanical signaling influences downstream signaling pathways involving stress‐activated protein kinases (JNK and p38) and survival/growth‐mediated pathways, such as Akt, which further regulate and modify cardiac fibroblast function to meet the demands of the extracellular environment.


Figure 9. Effects of IL‐1 on cardiac fibroblast signaling and function. Activation of the IL‐1 receptor in cardiac fibroblasts results in activation of MAPK signaling cascades (ERK, JNK, and p38) and NFκB, which modulate the expression of specific genes in cardiac fibroblasts that promote angiogenesis, inflammation, and cell migration, as well a degradation of the ECM.


Figure 10. The circulating and local cardiac renin angiotensin system. Angiotensin II (Ang II), the biologically active product of the renin‐angiotensin system (RAS,) has been demonstrated to play an important role in heart failure and cardiac hypertrophy. Classically, the RAS has been viewed as an endocrine system, in which the liver, kidney, and lung have participated in the production of Ang II through the production of angiotensinogen, rennin, and angiotensin converting enzyme (ACE), respectively. This view has been modified since several components of the RAS are now known to be produced by several peripheral tissues, including the heart. Both cardiac myocytes and fibroblasts have been demonstrated to generate all components of the RAS, as well as additional factors, such as tonin and chymase. This circulating RAS appears to be most important for overall vascular tone and salt and water balance, whereas the local cardiac RAS is thought to be important for regulating both physiologic and pathologic function in the heart. In cardiac fibroblasts, activation of the AT1 receptor has been demonstrated to stimulate cardiac remodeling via inducing gene expression of collagen, MMPs, TIMPs, cytokines, growth factors, as well as positive feedback for increased production of RAS components.


Figure 11. Effects of IL‐6 on cardiac fibroblast signaling and function. Activation of the IL‐6 cell surface receptor in cardiac fibroblasts leads to activation of associated Janus kinases (JAK), and in turn tyrosine phosphorylation of the receptors, and recruitment and tyrosine phosphorylation of signal transducer and activator of transcription (STAT) molecules. Different protein tyrosine phosphatases, such as SHP‐1can attenuate JAK activation by dephosphorylation. SHP‐1 associates through their SH2 domains with the IL‐6 receptor and can modulate JAK activation. Tyrosine phosphorylated STATs form dimers, which are capable of translocation to the nucleus, by reciprocal interaction of the (C‐terminally located) SH2 domains with the phosphotyrosine motifs. After translocation into the nucleus, the STAT dimers interact with the gamma interferon activation site (GAS) elements to induce target gene transcription associated with cardiac remodeling. Nuclear dephosphorylation of STATs by protein tyrosine phosphatases (PTPs) controls the amplitude and duration of STAT signaling. The dephosphorylated STAT molecules then become available for a new cycle of activation.


Figure 12. Cell communication in the heart. Cardiac fibroblasts and myocytes interact with both the extracellular matrix (ECM) and other cell types in the heart. Integrins and DDR2 are major receptor systems which interact with the ECM and couple to intracellular signaling pathways that regulate cellular function. Cardiac cell types can also interact through cell surface receptors, such as cadherins or more directly through gap junctions. Cell‐cell communication between cell types can take place through gap junctions, which are comprised of one or more types of connexins, allows for the exchange of ions and small molecules (e.g., small signaling proteins and/or microRNAs) between adjoining cells.


Figure 13. microRNA interplay between cells in the heart. Cell‐cell communication is important for proper development and maintaining normal cardiac function. Recent studies have demonstrated that miRNAs play a key role in cellular communication and in regulating gene expression and cellular functions. miRNAs can be trafficked multiple ways, in an intracellular or extracellular manner. Intracellular miRNA can have its effect on the host cell after being processed from pre‐miRNA to mature‐miRNA or it can be passed to an adjacent cell through tight gap junctions and have its effect on the adjacent cell. Extracellular miRNA can move into the bloodstream and have an effect on endothelial cells or distant cells and tissues. It can also be secreted into the ECM and be taken up by another cell.
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David Dostal, Shannon Glaser, Troy A. Baudino. Cardiac Fibroblast Physiology and Pathology. Compr Physiol 2015, 5: 887-909. doi: 10.1002/cphy.c140053