Laminins: Roles and Utility in Wound Repair

Abstract

Significance: Laminins are complex extracellular macromolecules that are major players in the control of a variety of core cell processes, including regulating rates of cell proliferation, differentiation, adhesion, and migration. Laminins, and related extracellular matrix components, have essential roles in tissue homeostasis; however, during wound healing, the same proteins are critical players in re-epithelialization and angiogenesis. Understanding how these proteins influence cell behavior in these different conditions holds great potential in identifying new strategies to enhance normal wound closure or to treat chronic/nonhealing wounds. Recent Advances: Laminin-derived bioactive peptides and, more recently, laminin-peptide conjugated scaffolds, have been designed to improve tissue regeneration after injuries. These peptides have been shown to be effective in decreasing inflammation and granulation tissue, and in promoting re-epithelialization, angiogenesis, and cell migration. Critical Issues: Although there is now a wealth of knowledge concerning laminin form and function, there are still areas of some controversy. These include the relative contribution of two laminin-based adhesive devices (focal contacts and hemidesmosomes) to the re-epithelialization process, the impact and implications of laminin proteolytic processing, and the importance of laminin polymer formation on cell behavior. In addition, the roles in wound healing of the laminin-related proteins, netrins, and LaNts are still to be fully defined. Future Directions: The future of laminin-based therapeutics potentially lies in the bioengineering of specific substrates to support laminin deposition for ex vivo expansion of autologous cells for graft formation and transplantation. Significant recent advances suggest that this goal is within sight.

Kevin J. Hamill, PhD, BSc

Figure 1.

Diagrammatic representation of laminins and laminin-related proteins involved in wound repair. Schematic depicting structural features of laminins expressed by epithelial and endothelial cells. Open triangles denote processing points; LN (coloured circles), laminin N-terminal domain; LE, laminin-type epidermal growth factor-like repeats; L4/LF, laminin globular domains; LCC, laminin coiled coil; LG, laminin globular domains. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

LM332 is upregulated at the leading front of migrating epithelial sheets and promotes rapid migration over the wounded surface. Hemidesmosome (HD) and focal adhesion (FA) proteins localize toward the leading front of migrating keratinocytes. LM332 then terminates vascularized granulation tissue formation via signaling from the N-terminal part of laminin α3A. In laryngo-onycho-cutaneous (LOC) syndrome, this signal is absent and leads to excessive vascularized granulation tissue formation. In junctional epidermolysis bullosa (JEB), loss of function mutations in any of the LM332 encoding genes leads to skin fragility. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

LaNts and netrins putative influence on laminin network formation. Laminin polymerization requires ternary node formation between LN domains from an α, a β, and a γ LN domain. Netrin-4 and possibly the LaNts may compete for these interactions, destabilizing the network. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

LaNt α31 decorates regions of LM332 deposition in migrating epidermal keratinocytes. Human epidermal keratinocytes were plated overnight on glass coverslips, then fixed, and processed for indirect immunofluorescence microscopy with antibodies against LaNt α31 (magenta, left), or LM332 (green, middle). Phase-contrast image of cells to the right. Scale bar 20 μm. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 5.

Location of laminin-derived peptides described in the text. Schematic representation of archetypal laminin with laminin chain, structural location, and function of peptide sequences indicated. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound