Epithelial injury and repair processes. Among the causes of epithelial injury are infections, inflammation, toxic compounds, and trauma. Several mechanisms are then sequentially engaged in epithelial repair: spreading, dedifferentiation, and migration of healthy epithelial cells, followed by proliferation and redifferentiation of progenitor cells. Inset : ␣ - and ␤ -integrin heterodimers link actin filaments to the extracellular matrix (ECM), favoring protrusion of the front edge of migrating cells, while proteinases [matrix metalloproteinase (MMP) and a disintegrin and metalloprotease domain (ADAM)] degrade the ECM, decreasing cell adhesion and promoting retraction of the rear edge of migrating cells. MMPs are also involved in release of growth factors, such as EGF. Moreover, integrin and EGF receptor (EGFR) trigger intracellular signaling, which is crucial for cell migration and proliferation. 

Epithelial injury and repair processes. Among the causes of epithelial injury are infections, inflammation, toxic compounds, and trauma. Several mechanisms are then sequentially engaged in epithelial repair: spreading, dedifferentiation, and migration of healthy epithelial cells, followed by proliferation and redifferentiation of progenitor cells. Inset : ␣ - and ␤ -integrin heterodimers link actin filaments to the extracellular matrix (ECM), favoring protrusion of the front edge of migrating cells, while proteinases [matrix metalloproteinase (MMP) and a disintegrin and metalloprotease domain (ADAM)] degrade the ECM, decreasing cell adhesion and promoting retraction of the rear edge of migrating cells. MMPs are also involved in release of growth factors, such as EGF. Moreover, integrin and EGF receptor (EGFR) trigger intracellular signaling, which is crucial for cell migration and proliferation. 

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Efficient repair of the epithelial tissue, which is frequently exposed to insults, is necessary to maintain its functional integrity. It is therefore necessary to better understand the biological and molecular determinants of tissue regeneration and to develop new strategies to promote epithelial repair. Interestingly, a growing body of evidence in...

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Context 1
... TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium ( Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these EPITHELIAL TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium (Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these Covering epithelial tissue, lining the outside surface of the body (skin and cornea) and the lumen of internal organs (gastrointestinal, urinary, and respiratory tracts), is frequently exposed to insults from external (e.g., pathogens, noxious chemicals, mechanical stress, and trauma) and internal (e.g., sepsis, ischemia-reperfusion, and exacerbated/chronic immune and inflammatory responses) sources. These aggressions trigger cascades of cellular events, culminating in epithelial damage and/or remodeling. The nature and severity of morpholog- ical/histological alterations may vary, depending on the source, duration (acute vs. chronic), and intensity of the injury and epithelium localization/type. However, despite this diversity, epithelial tissue will usually respond to damage by engaging multiple cellular events, including cell adhesion, migration, proliferation, and differentiation processes, in an attempt to restore its structural and functional integrity (Fig. 1). Cell migration is one of the first mechanisms of epithelial repair. This complex phenomenon integrates well-established processes, including cytoskeleton reorganization, membrane protrusion formation, and focal adhesion to the extracellular matrix (ECM) at the front edge and release of adhesion sites ...
Context 2
... TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium ( Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these EPITHELIAL TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium (Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these Covering epithelial tissue, lining the outside surface of the body (skin and cornea) and the lumen of internal organs (gastrointestinal, urinary, and respiratory tracts), is frequently exposed to insults from external (e.g., pathogens, noxious chemicals, mechanical stress, and trauma) and internal (e.g., sepsis, ischemia-reperfusion, and exacerbated/chronic immune and inflammatory responses) sources. These aggressions trigger cascades of cellular events, culminating in epithelial damage and/or remodeling. The nature and severity of morpholog- ical/histological alterations may vary, depending on the source, duration (acute vs. chronic), and intensity of the injury and epithelium localization/type. However, despite this diversity, epithelial tissue will usually respond to damage by engaging multiple cellular events, including cell adhesion, migration, proliferation, and differentiation processes, in an attempt to restore its structural and functional integrity (Fig. 1). Cell migration is one of the first mechanisms of epithelial repair. This complex phenomenon integrates well-established processes, including cytoskeleton reorganization, membrane protrusion formation, and focal adhesion to the extracellular matrix (ECM) at the front edge and release of adhesion sites ...
Context 3
... TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium ( Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these EPITHELIAL TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium (Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these Covering epithelial tissue, lining the outside surface of the body (skin and cornea) and the lumen of internal organs (gastrointestinal, urinary, and respiratory tracts), is frequently exposed to insults from external (e.g., pathogens, noxious chemicals, mechanical stress, and trauma) and internal (e.g., sepsis, ischemia-reperfusion, and exacerbated/chronic immune and inflammatory responses) sources. These aggressions trigger cascades of cellular events, culminating in epithelial damage and/or remodeling. The nature and severity of morpholog- ical/histological alterations may vary, depending on the source, duration (acute vs. chronic), and intensity of the injury and epithelium localization/type. However, despite this diversity, epithelial tissue will usually respond to damage by engaging multiple cellular events, including cell adhesion, migration, proliferation, and differentiation processes, in an attempt to restore its structural and functional integrity (Fig. 1). Cell migration is one of the first mechanisms of epithelial repair. This complex phenomenon integrates well-established processes, including cytoskeleton reorganization, membrane protrusion formation, and focal adhesion to the extracellular matrix (ECM) at the front edge and release of adhesion sites ...
Context 4
... TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium ( Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these EPITHELIAL TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium (Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these Covering epithelial tissue, lining the outside surface of the body (skin and cornea) and the lumen of internal organs (gastrointestinal, urinary, and respiratory tracts), is frequently exposed to insults from external (e.g., pathogens, noxious chemicals, mechanical stress, and trauma) and internal (e.g., sepsis, ischemia-reperfusion, and exacerbated/chronic immune and inflammatory responses) sources. These aggressions trigger cascades of cellular events, culminating in epithelial damage and/or remodeling. The nature and severity of morpholog- ical/histological alterations may vary, depending on the source, duration (acute vs. chronic), and intensity of the injury and epithelium localization/type. However, despite this diversity, epithelial tissue will usually respond to damage by engaging multiple cellular events, including cell adhesion, migration, proliferation, and differentiation processes, in an attempt to restore its structural and functional integrity (Fig. 1). Cell migration is one of the first mechanisms of epithelial repair. This complex phenomenon integrates well-established processes, including cytoskeleton reorganization, membrane protrusion formation, and focal adhesion to the extracellular matrix (ECM) at the front edge and release of adhesion sites ...
Context 5
... TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium ( Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these EPITHELIAL TISSUE acts as a protective barrier and plays a major processes. Covering Finally, epithelial we tissue, report some lining data the indicating outside surface a protective of the role in ion and liquid homeostasis. This tissue is exposed to body role of (skin K ϩ and channels cornea) after and injury the lumen in vivo of and internal discuss organs the frequent aggressions, which may cause acute or chronic inju- challenges (gastrointestinal, to efficient, urinary, specific, and respiratory and safe tracts), targeting is frequently of K ϩ ries and also trigger tissue remodeling. Epithelial regeneration, channels exposed to for insults therapeutic from applications external (e.g., to pathogens, improve epithelial noxious necessary to restore epithelial integrity and function, depends regeneration. chemicals, mechanical stress, and trauma) and internal (e.g., on several processes that are engaged sequentially after injury, sepsis, ischemia-reperfusion, and exacerbated/chronic immune including cell migration, proliferation, and differentiation, to and inflammatory responses) sources. These aggressions trig- restore a polarized and functional epithelium (Fig. 1) (16, 32, ger cascades of cellular events, culminating in epithelial dam- 61). These complex processes integrate many proteins and age and/or remodeling. The nature and severity of morpholog- mechanisms, which are regulated by various components, in- ical/histological alterations may vary, depending on the source, cluding growth factors and downstream signaling effectors (32, duration (acute vs. chronic), and intensity of the injury and 61). Another class of proteins, i.e., K ϩ channels, that exert epithelium localization/type. However, despite this diversity, their main recognized function in epithelia as the control of epithelial tissue will usually respond to damage by engaging membrane potential and the maintenance of driving force for multiple cellular events, including cell adhesion, migration, transepithelial ion/liquid transport (11, 14, 53) seems also to proliferation, and differentiation processes, in an attempt to regulate cell migration and proliferation processes of various restore its structural and functional integrity (Fig. 1). cell types, including epithelial cells. Cell migration is one of the first mechanisms of epithelial The purpose of our review is, first, to briefly summarize the repair. This complex phenomenon integrates well-established major mechanisms and proteins responsible for epithelial re- processes, including cytoskeleton reorganization, membrane pair. We then report evidence demonstrating that K ϩ channels protrusion formation, and focal adhesion to the extracellular are involved in the regulation of repair processes, especially matrix (ECM) at the front edge and release of adhesion sites at cell migration and proliferation. We also present an overview of the mechanisms whereby K ϩ channels may control these Covering epithelial tissue, lining the outside surface of the body (skin and cornea) and the lumen of internal organs (gastrointestinal, urinary, and respiratory tracts), is frequently exposed to insults from external (e.g., pathogens, noxious chemicals, mechanical stress, and trauma) and internal (e.g., sepsis, ischemia-reperfusion, and exacerbated/chronic immune and inflammatory responses) sources. These aggressions trigger cascades of cellular events, culminating in epithelial damage and/or remodeling. The nature and severity of morpholog- ical/histological alterations may vary, depending on the source, duration (acute vs. chronic), and intensity of the injury and epithelium localization/type. However, despite this diversity, epithelial tissue will usually respond to damage by engaging multiple cellular events, including cell adhesion, migration, proliferation, and differentiation processes, in an attempt to restore its structural and functional integrity (Fig. 1). Cell migration is one of the first mechanisms of epithelial repair. This complex phenomenon integrates well-established processes, including cytoskeleton reorganization, membrane protrusion formation, and focal adhesion to the extracellular matrix (ECM) at the front edge and release of adhesion sites ...
Context 6
... rear edge of migrating cells ( Fig. 1) (74). Cell movement on ognized cell volume/shape, functions of and epithelial membrane K potential), channels. proteins K channels, (e.g., provisional ECM and on denuded basement membranes de- coded integrins by and ϳ 90 cyclins), different and genes, signaling belong pathways to the largest (22, 44, ion 73, channel 100, pends on a fine equilibrium via concerted actions of adhesion family 106, 127, and 135, are widely 165). Growth expressed factors in all [e.g., organs. EGF, An transforming impressive and de-adhesion proteins (e.g., cadherin, integrins, and pro- number growth factor( ϳ 60) ␣ , of and different hepatocyte K ϩ channel growth factor subtypes (HGF)] have play been a teases) (4, 52, 56, 71, 75, 139). Indeed, numerous matrix prominent detected in role epithelial by acting cells via (Fig. 2). paracrine Only and/or pore-forming autocrine ␣ path- -sub- metalloproteinases (MMPs) and a disintegrin and metallopro- units ways are and represented downstream on signaling phylogenic cascades, trees inducing in Fig. 2; mitogenic, however, tease domain (ADAM) are involved in ECM remodeling, as numerous as well as auxiliary motogenic ␤ -subunits and morphogenic, are involved cellular in the responses formation (48, of well as in release of growth factors, regulating repair processes 90, 144, 145, 151, 165). (46, 75, 81, 110, 168). Integrins not only create links between Thus a large number of studies have contributed to knowl- the ECM and the cytoskeleton, but they also interact with edge of the mechanisms responsible for epithelial repair and have multiple proteins [e.g., EGF receptor (EGFR), focal adhesion identified major proteins, factors, and signaling pathways regulat- kinase (FAK), Src, and MEK/ERK] to trigger signaling path- ing them. However, in addition to these well-defined components, ways regulating repair mechanisms (4, 22, 52, 71, 139). other regulators of epithelial repair have emerged during the last Subsequent phases that promote healing comprise cell pro- two decades. Among them, ion channels and transporters have liferation and differentiation. The nature and turnover of cells, been shown to modulate the migration and proliferation of regarded as progenitors for natural renewal or regeneration many cells. In the following sections, we present proof of the after damage, are varied, depending on the epithelial tissue role of K ϩ channels in the control of repair processes, focusing studied. Epithelial tissue of the skin, cornea, and intestine is particularly on epithelial cells. characterized by continuous renewal through migration and proliferation of progenitor cells. In contrast, the rate of alveolar type (AT) II cell turnover in alveoli is low, and most ATII cells are quiescent in healthy adult lungs (148). However, these cells have the potential to dedifferentiate, proliferate (1, 24, 89, 136), and then redifferentiate into ATI or ATII cells (148) for alveolar restoration after injury. In fact, ongoing research is gradually identifying new stem cell niches participating in the regeneration of epithelial tissues. Cell migration, proliferation, and differentiation processes depend on many cellular events (Ca 2 ϩ signaling, changes in the rear edge of migrating cells (Fig. 1) (74). Cell movement on ognized cell volume/shape, functions of and epithelial membrane K potential), channels. proteins K channels, (e.g., provisional ECM and on denuded basement membranes de- coded integrins by and ϳ 90 cyclins), different and genes, signaling belong pathways to the largest (22, 44, ion 73, channel 100, pends on a fine equilibrium via concerted actions of adhesion family 106, 127, and 135, are widely 165). Growth expressed factors in all [e.g., organs. EGF, An transforming impressive and de-adhesion proteins (e.g., cadherin, integrins, and pro- number growth factor( ϳ 60) ␣ , of and different hepatocyte K ϩ channel growth factor subtypes (HGF)] have play been a teases) (4, 52, 56, 71, 75, 139). Indeed, numerous matrix prominent detected in role epithelial by acting cells via (Fig. 2). paracrine Only and/or pore-forming autocrine ␣ path- -sub- metalloproteinases (MMPs) and a disintegrin and metallopro- units ways are and represented downstream on signaling phylogenic cascades, trees inducing in Fig. 2; mitogenic, however, tease domain (ADAM) are involved in ECM remodeling, as numerous as well as auxiliary motogenic ␤ -subunits and morphogenic, are involved cellular in the responses formation (48, of well as in release of growth factors, regulating repair processes 90, 144, 145, 151, 165). (46, 75, 81, 110, 168). Integrins not only create links between Thus a large number of studies have contributed to knowl- the ECM and the cytoskeleton, but they also interact with edge of the mechanisms responsible for epithelial repair and have multiple proteins [e.g., EGF receptor (EGFR), focal adhesion identified major proteins, factors, and signaling pathways regulat- kinase (FAK), Src, and MEK/ERK] to trigger signaling path- ing them. However, in addition to these well-defined components, ways regulating repair mechanisms (4, 22, 52, 71, 139). other regulators of epithelial repair have emerged during the last Subsequent phases that promote healing comprise cell pro- two decades. Among them, ion channels and transporters have liferation and differentiation. The nature and turnover of cells, been shown to modulate the migration and proliferation of regarded as progenitors for natural renewal or regeneration many cells. In the following sections, we present proof of the after damage, are varied, depending on the epithelial tissue role of K ϩ channels in the control of repair processes, focusing studied. Epithelial tissue of the skin, cornea, and intestine is particularly on epithelial cells. characterized by continuous renewal through migration and proliferation of progenitor cells. In contrast, the rate of alveolar type (AT) II cell turnover in alveoli is low, and most ATII cells are quiescent in healthy adult lungs (148). However, these cells have the potential to dedifferentiate, proliferate (1, 24, 89, 136), and then redifferentiate into ATI or ATII cells (148) for alveolar restoration after injury. In fact, ongoing research is gradually identifying new stem cell niches participating in the regeneration of epithelial tissues. Cell migration, proliferation, and differentiation processes depend on many cellular events (Ca 2 ϩ signaling, changes in ognized functions of epithelial K channels. K channels, coded by ϳ 90 different genes, belong to the largest ion channel family and are widely expressed in all organs. An impressive number ( ϳ 60) of different K ϩ channel subtypes have been detected in epithelial cells (Fig. 2). Only pore-forming ␣ -subunits are represented on phylogenic trees in Fig. 2; however, numerous auxiliary ␤ -subunits are involved in the formation ...
Context 7
... rear edge of migrating cells ( Fig. 1) (74). Cell movement on ognized cell volume/shape, functions of and epithelial membrane K potential), channels. proteins K channels, (e.g., provisional ECM and on denuded basement membranes de- coded integrins by and ϳ 90 cyclins), different and genes, signaling belong pathways to the largest (22, 44, ion 73, channel 100, pends on a fine equilibrium via concerted actions of adhesion family 106, 127, and 135, are widely 165). Growth expressed factors in all [e.g., organs. EGF, An transforming impressive and de-adhesion proteins (e.g., cadherin, integrins, and pro- number growth factor( ϳ 60) ␣ , of and different hepatocyte K ϩ channel growth factor subtypes (HGF)] have play been a teases) (4, 52, 56, 71, 75, 139). Indeed, numerous matrix prominent detected in role epithelial by acting cells via (Fig. 2). paracrine Only and/or pore-forming autocrine ␣ path- -sub- metalloproteinases (MMPs) and a disintegrin and metallopro- units ways are and represented downstream on signaling phylogenic cascades, trees inducing in Fig. 2; mitogenic, however, tease domain (ADAM) are involved in ECM remodeling, as numerous as well as auxiliary motogenic ␤ -subunits and morphogenic, are involved cellular in the responses formation (48, of well as in release of growth factors, regulating repair processes 90, 144, 145, 151, 165). (46, 75, 81, 110, 168). Integrins not only create links between Thus a large number of studies have contributed to knowl- the ECM and the cytoskeleton, but they also interact with edge of the mechanisms responsible for epithelial repair and have multiple proteins [e.g., EGF receptor (EGFR), focal adhesion identified major proteins, factors, and signaling pathways regulat- kinase (FAK), Src, and MEK/ERK] to trigger signaling path- ing them. However, in addition to these well-defined components, ways regulating repair mechanisms (4, 22, 52, 71, 139). other regulators of epithelial repair have emerged during the last Subsequent phases that promote healing comprise cell pro- two decades. Among them, ion channels and transporters have liferation and differentiation. The nature and turnover of cells, been shown to modulate the migration and proliferation of regarded as progenitors for natural renewal or regeneration many cells. In the following sections, we present proof of the after damage, are varied, depending on the epithelial tissue role of K ϩ channels in the control of repair processes, focusing studied. Epithelial tissue of the skin, cornea, and intestine is particularly on epithelial cells. characterized by continuous renewal through migration and proliferation of progenitor cells. In contrast, the rate of alveolar type (AT) II cell turnover in alveoli is low, and most ATII cells are quiescent in healthy adult lungs (148). However, these cells have the potential to dedifferentiate, proliferate (1, 24, 89, 136), and then redifferentiate into ATI or ATII cells (148) for alveolar restoration after injury. In fact, ongoing research is gradually identifying new stem cell niches participating in the regeneration of epithelial tissues. Cell migration, proliferation, and differentiation processes depend on many cellular events (Ca 2 ϩ signaling, changes in the rear edge of migrating cells (Fig. 1) (74). Cell movement on ognized cell volume/shape, functions of and epithelial membrane K potential), channels. proteins K channels, (e.g., provisional ECM and on denuded basement membranes de- coded integrins by and ϳ 90 cyclins), different and genes, signaling belong pathways to the largest (22, 44, ion 73, channel 100, pends on a fine equilibrium via concerted actions of adhesion family 106, 127, and 135, are widely 165). Growth expressed factors in all [e.g., organs. EGF, An transforming impressive and de-adhesion proteins (e.g., cadherin, integrins, and pro- number growth factor( ϳ 60) ␣ , of and different hepatocyte K ϩ channel growth factor subtypes (HGF)] have play been a teases) (4, 52, 56, 71, 75, 139). Indeed, numerous matrix prominent detected in role epithelial by acting cells via (Fig. 2). paracrine Only and/or pore-forming autocrine ␣ path- -sub- metalloproteinases (MMPs) and a disintegrin and metallopro- units ways are and represented downstream on signaling phylogenic cascades, trees inducing in Fig. 2; mitogenic, however, tease domain (ADAM) are involved in ECM remodeling, as numerous as well as auxiliary motogenic ␤ -subunits and morphogenic, are involved cellular in the responses formation (48, of well as in release of growth factors, regulating repair processes 90, 144, 145, 151, 165). (46, 75, 81, 110, 168). Integrins not only create links between Thus a large number of studies have contributed to knowl- the ECM and the cytoskeleton, but they also interact with edge of the mechanisms responsible for epithelial repair and have multiple proteins [e.g., EGF receptor (EGFR), focal adhesion identified major proteins, factors, and signaling pathways regulat- kinase (FAK), Src, and MEK/ERK] to trigger signaling path- ing them. However, in addition to these well-defined components, ways regulating repair mechanisms (4, 22, 52, 71, 139). other regulators of epithelial repair have emerged during the last Subsequent phases that promote healing comprise cell pro- two decades. Among them, ion channels and transporters have liferation and differentiation. The nature and turnover of cells, been shown to modulate the migration and proliferation of regarded as progenitors for natural renewal or regeneration many cells. In the following sections, we present proof of the after damage, are varied, depending on the epithelial tissue role of K ϩ channels in the control of repair processes, focusing studied. Epithelial tissue of the skin, cornea, and intestine is particularly on epithelial cells. characterized by continuous renewal through migration and proliferation of progenitor cells. In contrast, the rate of alveolar type (AT) II cell turnover in alveoli is low, and most ATII cells are quiescent in healthy adult lungs (148). However, these cells have the potential to dedifferentiate, proliferate (1, 24, 89, 136), and then redifferentiate into ATI or ATII cells (148) for alveolar restoration after injury. In fact, ongoing research is gradually identifying new stem cell niches participating in the regeneration of epithelial tissues. Cell migration, proliferation, and differentiation processes depend on many cellular events (Ca 2 ϩ signaling, changes in ognized functions of epithelial K channels. K channels, coded by ϳ 90 different genes, belong to the largest ion channel family and are widely expressed in all organs. An impressive number ( ϳ 60) of different K ϩ channel subtypes have been detected in epithelial cells (Fig. 2). Only pore-forming ␣ -subunits are represented on phylogenic trees in Fig. 2; however, numerous auxiliary ␤ -subunits are involved in the formation ...

Citations

... Whereas early studies on membrane potential primarily focused on excitability, scientists have recently shown that dynamic membrane potential also exists in most nonexcitable cells, although its role is unclear. Emerging studies indicate that membrane potential is involved in a wide range of biological functions of cells, including the cell cycle of T cells, 36 proliferation of vascular smooth muscle cells, 37 volume control of chondrocytes, 38 secretion of pancreatic β cells, 39 migration of epithelial cells 40 , and circadian rhythm of fibroblasts. 41 Lallet-Daher et al. first reported alterations of plasma membrane potential in cell senescence. ...
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Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα, whereas its permeability to Na+ was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na+ by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca2+ influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.
... Hypoxic preconditioning of MSCs augments their migration through activation of Kv2.1 potassium channel and focal adhesion kinase (FAK) [153]. Potassium channel activity and its interaction with the cytoskeleton or integrin are essential for cell migration and homing process [154]. FAK is a cell membrane kinase that stimulates cell migration through interactions with other Src family mediators [155]. ...
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Cell-based therapy (CBT) is a revolutionary approach for curing a variety of degenerative diseases. Stem cell-based regenerative medicine is a novel strategy for treating tissue damages regarding stem cells unique properties such as differentiation potential, paracrine impacts, and self-renewal ability. However, the current cell-based treatments encounter considerable challenges to be translated into clinical practice, including low cell survival, migration, and differentiation rate of transplanted stem cells. The poor stem cell therapy outcomes mainly originate from the unfavorable condition of damaged tissues for transplanted stem cells. The promising method of preconditioning improves cell resistance against the host environment's stress by imposing certain conditions similar to the harsh microenvironment of the damaged tissues on the transplanted stem cells. Various pharmacological, biological, and physical inducers are able to establish preconditioning. In addition to their known pharmacological effects on tissues and cells, these preconditioning agents improve cell biological aspects such as cell survival, proliferation, differentiation, migration, immunomodulation, paracrine impacts, and angiogenesis. This review focuses on different protocols and inducers of preconditioning along with underlying molecular mechanisms of their effects on stem cell behavior. Moreover, preclinical applications of preconditioned stem cells in various damaged organs such as heart, lung, brain, bone, cartilage, liver, and kidney are discussed with prospects of their translation into the clinic.
... Accurate wound healing plays an important role in maintaining the homeostasis of the internal environment and preventing infection [19]. In epithelial contexts, wound healing consists of several cellular processes including cell migration, cell proliferation, and cell differentiation [20]. Upon tissue injury, cell migration first occurs with cells moving toward the damage site, which necessitates actin cytoskeleton reorganization and membrane protrusion formation such as lamellipodia [21]. ...
Article
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Medusozoans, the Cnidarian subphylum, have multiple life stages including sessile polyps and free-swimming medusae or jellyfish, which are typically bell-shaped gelatinous zooplanktons that exhibit diverse morphologies. Despite having a relatively complex body structure with well-developed muscles and nervous systems, the adult medusa stage maintains a high regenerative ability that enables organ regeneration as well as whole body reconstitution from the part of the body. This remarkable regeneration potential of jellyfish has long been acknowledged in different species; however, recent studies have begun dissecting the exact processes underpinning regeneration events. In this article, we introduce the current understanding of regeneration mechanisms in medusae, particularly focusing on cellular behaviors during regeneration such as wound healing, blastema formation by stem/progenitor cells or cell fate plasticity, and the organism-level patterning that restores radial symmetry. We also discuss putative molecular mechanisms involved in regeneration processes and introduce a variety of novel model jellyfish species in the effort to understand common principles and diverse mechanisms underlying the regeneration of complex organs and the entire body.
... However, LRRC8A knockdown in myoblast, colon cancer and glioblastoma cell lines showed no effect on proliferation [78], while others found an effect of LRRC8A on proliferation in hepatocellular carcinoma [79] or primary glioblastoma cells [80]. In addition, K + channels are involved in regulating cell migration and proliferation in epithelial cells through modulation of membrane potential, cell volume, intracellular Ca 2+ and various signaling pathways [81]. ...
Article
Full-text available
In order to cope with external stressors such as changes in humidity and temperature or irritating substances, the epidermis as the outermost skin layer forms a continuously renewing and ideally intact protective barrier. Under certain circumstances, this barrier can be impaired and epidermal cells have to counteract cell swelling or shrinkage induced by osmotic stress via regulatory volume decrease (RVD) or increase (RVI). Here, we will review the current knowledge regarding the molecular machinery underlying RVD and RVI in the epidermis. Furthermore, we will discuss the current understanding how cell volume changes and its regulators are associated with epidermal renewal and barrier formation.
... Potassium channels are found in all living organisms and represent the largest group of ion channels 42 . In both excitable and non-excitable cells, potassium channels regulate Ca2+ signaling, volume regulation, secretion, cell death, proliferation, migration, differentiation and most recently in skin wound healing 43,44 . ...
... For example, potassium channel openers and its ionophore, valinomycin enhanced skin wound healing, while potassium blockers delayed the wound healing after an acute insult of mouse skin 45 . Thus, potassium channels could be good potential therapeutic targets for wound repair and regeneration 42 . In this study, we examined the gene expression of potassium channels at amputated hind limbs of mouse embryos at E12.5 and E15.5. ...
Article
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Background: Ion channels are a large family of transmembrane proteins, accessible by soluble membrane-impermeable molecules, and thus are targets for development of therapeutic drugs. Ion channels are the second most common target for existing drugs, after G protein-coupled receptors, and are expected to make a big impact on precision medicine in many different diseases including wound repair and regeneration. Research has shown that endogenous bioelectric signaling mediated by ion channels is critical in non-mammalian limb regeneration. However, the role of ion channels in regeneration of limbs in mammalian systems is not yet defined. Methods: To explore the role of potassium channels in limb wound repair and regeneration, the hindlimbs of mouse embryos were amputated at E12.5 when the wound is expected to regenerate and E15.5 when the wound is not expected to regenerate, and gene expression of potassium channels was studied. Results: Most of the potassium channels were downregulated, except for the potassium channel kcnj8 (Kir6.1) which was upregulated in E12.5 embryos after amputation. Conclusion: This study provides a new mouse limb regeneration model and demonstrates that potassium channels are potential drug targets for limb wound healing and regeneration.
... Recently, K + channels have been reported to be key parameters of epithelial repair via regulating the epithelial cell motility and hence, promoting the cell migration and proliferation. 62 In-Vivo Wound Healing Performance A robust inflammatory response mediates a healthy healing process devoid of infection. 63 However, current emerging studies suggest that the depletion of one or more of the inflammatory cell lineages would augment the healing process. ...
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Objectives: Novel α-bisabolol (BIS)-loaded citric acid cross-linked zein nanofibrous scaffolds (C-ZNFs) were proposed to serve as safe platforms for promoting wound repair in rats. Methods: ZNFs were synthesized using electrospinning technique, then NFs, with adequate water resistance, were produced using citric acid as a safe cross-linker. Results: Compared to the uncross-linked ZNFs, cross-linking with 7% w/w citric acid decreased swelling index by 3 folds, while the tensile strength and the contact angle were enhanced to 2.5 and 3.8 folds, respectively. SEM images showed beads-free homogeneous NFs with a fully inter-connected 3D-network, where the average diameter of optimized C-ZNFs was 181.7±50 nm. After 24 h, C-ZNFs exhibited a decreased BIS release rate (45.6%), compared to uncross-linked mats (84.9%). By increasing BIS concentration, the cell adhesion (WI38 fibroblasts) was improved which can be attributed mainly to BIS activation of transforming growth factor-beta (TGF-β1). The MTT-OD obtained values indicated that all tested zein scaffolds significantly enhanced the viability of WI38 fibroblasts, compared to the control after 48h of incubation which can be referred to the proliferative potential of zein by provoking cell spreading process. The scratch wound assay demonstrated that BIS-loaded ZNF scaffolds showed accelerated migration and proliferation of fibroblasts expressed by significantly higher wound closure rates compared to the control sample. BIS-loaded-C-ZNFs prominently accelerated tissue regeneration for wound closure demonstrated by entirely grown epithelium with normal keratinization and rapid wound contraction, compared to the control. Immunohistochemical results confirmed the superiority of BIS-loaded-C-ZNFs, where the observed reduced NF-κB and the elevated cytokeratin expressions confirmed the anti-inflammatory and proliferative effects of the scaffolds, respectively. Conclusion: In-vitro, optimized C-ZNFs offered a satisfactory cytocompatibility, adhesion and healing which were consistent with the in-vivo results. BIS-loaded-C-ZNFs could be regarded as a promising and effective biomaterial for tissue regeneration and for accelerating the wound healing process.
... ABCC9 is also known as the sulfonylurea receptor 2 (SUR2) protein and functions as an ATP sensitive K + channel that helps coordinate calcium levels in skeletal and cardiac muscle 52,53 . Reduced ABCC9 levels could conceivably dysregulate K + and calcium concentrations within airway epithelial cells, which in turn could impact K + regulated mechanisms of epithelial cell migration, proliferation, and tissue repair 54 . Irrespective of the proposed functions of these ABC transporters that are differentially expressed in epithelial cells from asthmatics, we can conclude that the different patterns observed in cells from asthmatics, smokers, or individuals with COPD suggests that regulation and function of ABC transporters is specific to a given chronic inflammatory lung disease or environmental insult. ...
Article
Full-text available
ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. We used a bioinformatic approach complemented with in vitro experimental methods for validation of the 48 known human ABC transporters in airway epithelial cells using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma, with validation performed in Calu-3 airway epithelial cells. Gene expression data demonstrate that ABC transporters are variably expressed in epithelial cells from different airway generations, regulated by cigarette smoke exposure (ABCA13, ABCB6, ABCC1, and ABCC3), and differentially expressed in individuals with COPD and asthma (ABCA13, ABCC1, ABCC2, ABCC9). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate select observed in situ changes. Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.
... ABCC9 is also known as the sulfonylurea receptor 2 (SUR2) protein and functions as an ATP sensitive K+ channel that helps coordinate calcium levels in skeletal and cardiac muscle 51,52 . Reduced ABCC9 levels could conceivably dysregulate K+ and calcium concentrations within airway epithelial cells, which in turn could impact K+ regulated mechanisms of epithelial cell migration, proliferation, and tissue repair 53 . Irrespective of the proposed functions of these ABC transporters that are differentially expressed in epithelial cells from asthmatics, we can conclude that the different patterns observed in cells from asthmatics, smokers, or individuals with COPD suggests that regulation and function of ABC transporters is specific to a given chronic inflammatory lung disease or environmental insult. ...
Preprint
Rationale The respiratory mucosa coordinates responses to infections, allergens, and exposures to air pollution. A relatively unexplored aspect of the respiratory mucosa are the expression and function of ATP Binding Cassette (ABC) transporters. ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. A deeper exploration of the expression patterns of ABC transporters in the respiratory mucosa is warranted to determine their relevance in lung health and disease. Methods We used a bioinformatic approach complemented with in vitro experimental methods for validation of candidate ABC transporters. We analyzed the expression profiles of all 48 human ABC transporters in the respiratory mucosa using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. The Calu-3 airway epithelial cell line was used to interrogate selected results using a cigarette smoke extract exposure model. Results Using 9 distinct gene-expression datasets of primary human airway epithelial cells, we completed a focused analysis on 48 ABC transporters in samples from healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. In situ gene expression data demonstrate that ABC transporters are i) variably expressed in epithelial cells from different airway generations (top three expression levels - ABCA5, ABCA13 , and ABCC5) , ii) regulated by cigarette smoke exposure ( ABCA13 , ABCB6 , ABCC1 , and ABCC3 ), and iii) differentially expressed in individuals with COPD and asthma ( ABCA13 , ABCC1 , ABCC2 , ABCC9 ). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate the in situ changes observed in cigarette smokers for ABCA13 and ABCC1 . Conclusions Our in situ human gene expression data analysis reveals that ABC transporters are expressed throughout the airway generations in airway epithelial cells and can be modulated by environmental exposures important in chronic respiratory disease (e.g. cigarette smoking) and in individuals with chronic lung diseases (e.g. COPD or asthma). Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.
... 58 Polymorphisms in 2 potassium channels have also been postulated to be implicated in the pathogenesis of CRS in children. 59 This might also affect epithelial repair because several studies, including from our group, 37,60,61 have demonstrated that potassium channels are essential for epithelial cell migration and proliferation and key processes for airway epithelial repair. ...
Article
Full-text available
Background: The impact of Staphylococcus aureus (SA) on nasal epithelial repair has never been assessed in chronic rhinosinusitis with nasal polyps (CRSwNP). Objective: This study aimed to determine whether: i) nasal epithelial cell cultures from patients with CRSwNP and control subjects repair differently; ii) SA exoproducts compromise nasal epithelial repair; iii) SA alters lamellipodial dynamics; and iv) deleterious effects could be counteracted by the ROCK inhibitor Y-27632. Methods: Primary nasal epithelial cells (pNECs), collected during surgeries, were cultured and injured under three conditions: i) basal, ii) exposed to SA exoproducts, and iii) exposed to SA exoproducts and Y-27632. Epithelial repair, lamellipodial dynamics and cytoskeletal organization were assessed. Results: Under basal condition, pNECs cultures from CRSwNP presented significantly lower repair rates, and reduced lamellipodial protrusion length and velocity than controls. SA exoproducts significantly decreased repair rates and protrusion dynamics in both controls and CRSwNP, however, the effect of SA on cell protrusions was more sustained over time in CRSwNP. Under basal conditions, immunofluorescence assays showed significantly reduced percentage of cells with lamellipodia at the wound edge in CRSwNP as compared to controls. SA altered cell polarity and decreased the percentage of cells with lamellipodia in both groups. Finally, Y-27632 prevented the deleterious effects of SA exoproducts on CRSwNP repair rates as well as on lamellipodial dynamics and formation. Conclusions: SA exoproducts significantly alter epithelial repair and lamellipodial dynamics on pNECs, this impairment was more pronounced in CRSwNP. Importantly, Y-27632 restored epithelial repair and lamellipodial dynamics in the presence of SA exoproducts. Clinical implications: Sinonasal epithelia from CRSwNP exhibit a defect in wound healing compared to controls, which is worsened by exposure to S. aureus. This phenomenon may be prevented by ROCK targeted therapies.
... This localized change of volume is due to specific local K + (mainly through BK channels), Cl -(ClC-3 channels) and water fluxes in the invadopodia, the dynamic actin-rich membrane structures, permitting cell migration and invasion in the neighbouring tissue; BK and ClC-3 co-localize in the lipid-raft domains of invadopodia, both contributing to ions efflux [6]. Channels involved in this process are voltagegated K + channels [7][8][9] and, mainly, Ca 2+ activated K + channels [9][10][11]. This mechanism is further strengthened by the activity of a Na + /H + pumps at the leading edge and of aquaporin channels at the trailing one [12]. ...
Article
Full-text available
Background: Glioblastoma is the most aggressive and deadly brain tumor, with low disease-free period even after surgery and combined radio and chemotherapies. Among the factors contributing to the devastating effect of this tumor in the brain are the elevated proliferation and invasion rate, and the ability to induce a local immunosuppressive environment. The intermediateconductance Ca2+-activated K+ channel KCa3.1 is expressed in glioblastoma cells and in tumorinfiltrating cells. Methods: We first describe the researches related to the role of KCa3.1 channels in the invasion of brain tumor cells and the regulation of cell cycle. In the second part we review the involvement of KCa3.1 channel in tumor-associated microglia cell behaviour. Results: In tumor cells, the functional expression of KCa3.1 channels is important to substain cell invasion and proliferation. In tumor infiltrating cells, KCa3.1 channel activity is required to regulate their activation state. Interfering with KCa3.1 activity can be an adjuvant therapeutic approach in addition to classic chemotherapy and radiotherapy, to counteract tumor growth and prolong patient's survival. Conclusion: In this mini-review we discuss the evidence of the functional roles of KCa3.1 channels in glioblastoma biology.