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Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis.

Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Misra S - Int J Cell Biol (2015)

Bottom Line: Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis).Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes.Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
A wound is a type of injury that damages living tissues. In this review, we will be referring mainly to healing responses in the organs including skin and the lungs. Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis). In tissues such as the skin, the repair of the dermis after wounding requires not only the fibroblasts that produce the ECM molecules, but also the overlying epithelial layer (keratinocytes), the endothelial cells, and smooth muscle cells of the blood vessel and white blood cells such as neutrophils and macrophages, which together orchestrate the cytokine-mediated signaling and paracrine interactions that are required to regulate the proper extent and timing of the repair process. This review will focus on the importance of extracellular molecules in the microenvironment, primarily the proteoglycans and glycosaminoglycan hyaluronan, and their roles in wound healing. First, we will briefly summarize the physiological, cellular, and biochemical elements of wound healing, including the importance of cytokine cross-talk between cell types. Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes. Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

No MeSH data available.


Related in: MedlinePlus

Structures of repeating disaccharides of glycosaminoglycans.
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Related In: Results  -  Collection


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fig3: Structures of repeating disaccharides of glycosaminoglycans.

Mentions: Of the various ECM macromolecules, the GAG side-chains of PGs are very important players in wound healing. GAG chains (Figure 3) exhibit considerable structural diversity resulting from a complex biosynthesis that is tightly regulated in biological systems, enabling the modified GAGs to selectively interact with a variety of ligands in a spatially and temporally controlled manner [56, 57]. During the proliferation phase of wound healing, fibroblasts and other mesenchymal cells enter the inflammatory site of the wound in response to growth factors that are necessary for stimulation of cell proliferation [58]. The fibroblasts synthesize collagen and PGs, which continues for several weeks with proportional increases of collagen. During this time, endothelial cells form capillaries, and the GAGs (HA, chondroitin sulfate (CS), and dermatan sulfate (DS)) also change in their levels. Initially, HA is synthesized in large amounts by the fibroblasts for 2 weeks [26], followed by increased levels of DS and CS PGs [59]. Gradually, when the proliferation of cells reaches a plateau, heparan sulfate (HS) PGs are elevated in the wound. Sulfated PGs with CS and DS assist in collagen polymerization [60], and HS PGs on cells can create anchors to surrounding matrix [61]. PG degradation by proteases in the wounds can release GAG-peptide fragments, which may modulate the wound healing process [62]. For instance, CS and DS can regulate growth factor activity and may stimulate nitric oxide production, which, in turn, can modulate angiogenesis, whereas HS can stimulate the release of IL-1, IL-6, PGE2, and TGF-β and contribute to the modulation of its proangiogenic effects in the tissues [63, 64]. Studies have demonstrated colocalization of the large CS PG versican with HA in cables in smooth muscle cells [65] and in an epithelial cell system [66]. Of the GAGs, HA has a key role in each phase of wound healing as well as in regulating ECM organization and metabolism [67].


Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis.

Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Misra S - Int J Cell Biol (2015)

Structures of repeating disaccharides of glycosaminoglycans.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581578&req=5

fig3: Structures of repeating disaccharides of glycosaminoglycans.
Mentions: Of the various ECM macromolecules, the GAG side-chains of PGs are very important players in wound healing. GAG chains (Figure 3) exhibit considerable structural diversity resulting from a complex biosynthesis that is tightly regulated in biological systems, enabling the modified GAGs to selectively interact with a variety of ligands in a spatially and temporally controlled manner [56, 57]. During the proliferation phase of wound healing, fibroblasts and other mesenchymal cells enter the inflammatory site of the wound in response to growth factors that are necessary for stimulation of cell proliferation [58]. The fibroblasts synthesize collagen and PGs, which continues for several weeks with proportional increases of collagen. During this time, endothelial cells form capillaries, and the GAGs (HA, chondroitin sulfate (CS), and dermatan sulfate (DS)) also change in their levels. Initially, HA is synthesized in large amounts by the fibroblasts for 2 weeks [26], followed by increased levels of DS and CS PGs [59]. Gradually, when the proliferation of cells reaches a plateau, heparan sulfate (HS) PGs are elevated in the wound. Sulfated PGs with CS and DS assist in collagen polymerization [60], and HS PGs on cells can create anchors to surrounding matrix [61]. PG degradation by proteases in the wounds can release GAG-peptide fragments, which may modulate the wound healing process [62]. For instance, CS and DS can regulate growth factor activity and may stimulate nitric oxide production, which, in turn, can modulate angiogenesis, whereas HS can stimulate the release of IL-1, IL-6, PGE2, and TGF-β and contribute to the modulation of its proangiogenic effects in the tissues [63, 64]. Studies have demonstrated colocalization of the large CS PG versican with HA in cables in smooth muscle cells [65] and in an epithelial cell system [66]. Of the GAGs, HA has a key role in each phase of wound healing as well as in regulating ECM organization and metabolism [67].

Bottom Line: Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis).Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes.Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
A wound is a type of injury that damages living tissues. In this review, we will be referring mainly to healing responses in the organs including skin and the lungs. Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis). In tissues such as the skin, the repair of the dermis after wounding requires not only the fibroblasts that produce the ECM molecules, but also the overlying epithelial layer (keratinocytes), the endothelial cells, and smooth muscle cells of the blood vessel and white blood cells such as neutrophils and macrophages, which together orchestrate the cytokine-mediated signaling and paracrine interactions that are required to regulate the proper extent and timing of the repair process. This review will focus on the importance of extracellular molecules in the microenvironment, primarily the proteoglycans and glycosaminoglycan hyaluronan, and their roles in wound healing. First, we will briefly summarize the physiological, cellular, and biochemical elements of wound healing, including the importance of cytokine cross-talk between cell types. Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes. Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

No MeSH data available.


Related in: MedlinePlus