Abstract
Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)β signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.
Highlights
The skin, comprised of the epidermis, dermis, and deeper subcutaneous tissue, is the largest organ of the body, and functions as the first line of defense from external assaults (Proksch et al, 2008)
small leucine-rich proteoglycans (SLRPs) are important components of the extracellular matrix (ECM) that play crucial roles in collagen fibril growth, fibril organization, and ECM assembly. They are capable of modulating the function of a significant number of growth factors and cytokines and have even been thought to prevent fibrosis and organ dysfunction (Mecham, 2011; Schaefer, 2011; Klingberg et al, 2013)
Thanks to worldwide collaboration over the last 30 years, much has been discovered in regard to the pivotal roles that SLRPs play in the different phases of the skin wound healing process, as well as the therapeutic potentials of SLRPs for reducing scar formation
Summary
The skin, comprised of the epidermis, dermis, and deeper subcutaneous tissue, is the largest organ of the body, and functions as the first line of defense from external assaults (Proksch et al, 2008). Consisting of a core protein covalently attached with one or more glycosaminoglycan (GAG) chains, PGs play a pivotal role in the proper alignment of fibrous and elastic components in the skin and control the bioavailability of several growth factors in the ECM surrounding cells to stimulate the skin turnover and repair (Mary and James, 2015) Based on their structure, location, and properties, PGs can be divided into 4 classes: intracellular PGs, basement membrane PGs, cell-surface PGs, and extracellular PGs (Vynios, 2014; Iozzo and Schaefer, 2015). Small leucine-rich proteoglycans (SLRPs), constitute another large family of extracellular PGs (Pietraszek-Gremplewicz et al, 2019) that play a pivotal role in collagen fibril growth, fibril organization, and ECM assembly in healthy skin (Merline et al, 2009; Chen and Birk, 2013). SLRPs in the skin, their relationship with human skin pathologies, and current understandings of their roles in skin wound healing to gain insights into their potentials as wound healing management pharmaceuticals
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