Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis

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.

Reactivating the extracellular matrix synthesis of sulfated glycosaminoglycans and proteoglycans to improve the human skin aspect and its mechanical properties

“…As the stability and synthesis of GAGs and proteoglycans found in skin are known to be sensitive to ultraviolet (UV),18 aging,19 and pathologies,20 a major challenge is to find a solution enabling to specifically reactivate the synthesis of these macromolecules to promote the spatial assembly of collagen and elastic fibers in a fashion similar to that observed in young skin.…”

Scarring vs. functional healing: Matrix-based strategies to regulate tissue repair

“…Glycosaminoglycans (GAGs) such as hyaluronic acid (HA), chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate (HS) are synthesized by fibroblasts and contribute to the hydrophilic granulation matrix [36, 37]. Proteoglycans consist of core proteins or glycoproteins with glycosamino side-chains that interact with granulation tissue, altering matrix biomechanical properties and hydrophobicity, and modifying cell migration and fate.…”

Minimizing Skin Scarring through Biomaterial Design

“…Additionally, the formation of platelet plugs serve as an ECM substitute, providing a scaffold for inflammatory cells to enter the wound bed [2]. The platelet plug also serves as a mechanical barrier to the external environment, comprised of proteins like fibronectin, vitronectin, thrombospondin, and SPARC (secreted protein, acidic and rich in cysteine), which will similarly aid in the recruitment of inflammatory cells and bind other ECM molecules together [20]. The ECM will ultimately serve as an important shield, growth factor reservoir, and matrix to modulate wound healing with substances like hyaluronic acid, proteoglycans, glycosaminoglycans, and collagen [20].…”

“…The platelet plug also serves as a mechanical barrier to the external environment, comprised of proteins like fibronectin, vitronectin, thrombospondin, and SPARC (secreted protein, acidic and rich in cysteine), which will similarly aid in the recruitment of inflammatory cells and bind other ECM molecules together [20]. The ECM will ultimately serve as an important shield, growth factor reservoir, and matrix to modulate wound healing with substances like hyaluronic acid, proteoglycans, glycosaminoglycans, and collagen [20]. Interestingly, it is the ECM which is responsible for the initial recruitment of inflammatory cells through proteolytic cleavage of ECM-bound growth factors and cell-signaling molecules, bringing circulating inflammatory cells into the wound [21,22,23,24,25].…”

“…Vimentin and fibronectin are gradually replaced with type I collagen, which will serve as the ultimate scar substrate [2,28,47]. Additionally, the versican v3 isoform proteoglycan promotes the transition of fibroblasts into myofibroblasts, the cells responsible for collagen contraction [20]. Of note, there is significant heterogeneity between fibroblasts that has only recently been described [48].…”