The Yin and Yang of Integrin Function in Re-Epithelialization During Wound Healing

Abstract

Background: Integrins are transmembrane proteins that are present in the plasma membrane of basal ketatinocytes and connect them to the underlying basement membrane and to the dermis. There are primarily two types of interactions between the epidermis and the dermis-via focal adhesion plaques and hemidesmosomes. It is critical that these interactions form properly to confer the skin strong mechanical properties. Integrins are also critical during wound healing, particularly in closure of the wound.

The problem: Margadant et al. (2009) address proper closure of cutaneous wounds. They developed a conditional knockout mouse for integrin α₃ and showed that the absence of the α₃ integrin resulted in faster migration of the keratinocytes during wound healing. However, its absence also led to inflammation, hair loss, basement membrane duplication, and loss of dermal epidermal interactions with blister formation. The latter has important consequences for the ability of the skin to withstand mechanical challenges.

Basic/clinical science advances: Models such as the conditional model developed by Margadant et al. (2009) will provide the opportunity for making major advances in understanding the complex function of integrins during healing.

Clinical care relevance: The model and the findings provide an opportunity to decipher mechanisms of disease and for potential development of treatments for human skin disorders and impaired healing, including chronic ulcers.

Conclusion: This work provides knowledge that leads to the understanding of delayed re-epithelialization during wound healing and dermal epidermal defects, blistering, and chronic skin diseases, hence providing the opportunity to understand the basic cellular and molecular mechanisms involved in these situations.

Manuela Martins-Green, PhD

Figure 1.

Integrin family members: members of the integrin family of ECM receptors and their respective ligands are shown. These heterodimeric receptors are composed of one α and one β subunit and are capable of binding a variety of ligands, including Ig superfamily cell adhesion molecules, complement factors, and clotting factors, in addition to ECM molecules. Cell–cell adhesion is largely mediated through integrin heterodimers containing the β₂ subunits, whereas cell–matrix adhesion is primarily mediated via integrin heterodimers containing the β₁ and β₃ subunits. In general, the β₁ integrins interact with ligands found in the connective tissue matrix, including LN, FN, and collagen, whereas the β₃ integrins interact with vascular ligands, including thrombospondin, vitronectin, fibrinogen, and von Willebrand factor. *RGD mediated binding. CO, collagens; C3bi, complement component; FG, fibrinogen; FN, fibronectin; FX, factor X; ICAM, intercellular adhesion molecule; LN, laminin; OSP, osteopontin; TN, tenascin; TSP, thrombospondin; VCAM, vascular cell adhesion molecule; VN, vitronectin; vWF, von Willebrand factor. Reprinted with permission from Dueck-Petreaca and Martins-Green (2007). Color images available online at www.liebertpub.com/wound

Figure 2.

Schematic representation of the basal keratinocyte interactions with the basement membrane and the dermis: two types of interactions are seen. One represents a focal adhesion type interaction and the other an anchoring-type interaction through hemidesmosomes. The focal adhesion involves α₃β₁, LN332, and critical proteins that link the integrin intracellular domains to the microfilament cytoskeleton. The hemidesmosome interaction involves α₆β₄, LN332, Coll XVII, and BP230 as well as pectin, which helps in the association of the intracellular domain of the integrin and the keratin cytoskeleton. Both adhesion complexes interact with Coll IV, perlecan, and nidogen in the lamina densa of the basal lamina and in turn interact with Coll VII and Coll I and III in the reticular lamina. V, vinculin; T, talin; αA, alpha actinin; BP, Bullous Pemphigoid. Color images available online at www.liebertpub.com/wound