The Roles of Growth Factors in Keratinocyte Migration

Abstract

Significance: The re-epithelialization of wounded skin requires the rapid and coordinated migration of keratinocytes (KC) into the wound bed. Almost immediately after wounding, cells present at or attracted to the wound site begin to secrete a complex milieu of growth factors. These growth factors exert mitogenic and motogenic effects on KCs, inducing the rapid proliferation and migration of KCs at the wound edge. Recent Advances: New roles for growth factors in KC biology are currently being discovered and investigated. This review will highlight the growth factors, particularly transforming growth factor-α (TGF-α), heparin-binding epidermal growth factor (HB-EGF), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 7 (FGF-7), FGF-10, and hepatocyte growth factor (HGF), which have conclusively been shown to be the most motogenic for KCs. Critical Issues: The cellular and molecular heterogeneity of wounded tissue makes establishing direct relationships between specific growth factors and KC migration difficult in situ. The absence of this complexity in simplified in vitro experimental models of migration makes the clinical relevance of the results obtained from these in vitro studies ambiguous. Future Directions: Deciphering the relationship between growth factors and KC migration is critical for understanding the process of wound healing in normal and disease states. Insights into the basic science of the effects of growth factors on KC migration will hopefully lead to the development of new therapies to treat acute and chronic wounds.

Amy S. Paller, MS, MD

Figure 1.

Representative images of migrating single keratinocytes (KCs) and sheets of KCs. (A) KCs with the typical morphology of an individual migrating KC: fan-shape morphology and extension of lamellipodia in the direction of migration (arrow). (B) A sheet of KCs in a scratch wound assay exhibits the typical morphology of collectively migrating KCs: maintenance of cell–cell contacts, and extension of lamellipodia into the wound site by cells along the leading edge in the direction of migration (arrow). (A. Paller, Department of Dermatology, Northwestern University, unpublished data).

Figure 2.

Receptors and ligands that have been shown to induce KC migration. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

Histologic (left panel) and schematic (right panel) representations of a healing full-thickness excisional wound in mouse skin outlining the distribution of motogenic growth factors during wound healing. Growth factors are secreted by a variety of cell types that are found distant from, adjacent to, and within the wound site. Growth factors originate from fibroblasts (FBs) and KCs, as well as from macrophages (MP), platelets (PL), leukocytes (LK), peripheral nervous system cells (PNS), pancreatic β-cells (PB), hepatocytes (HP), melanocytes (ML), and mesenchymal cells (MS). E, epidermis; HF, hair follicle; D, dermis; A, adipose tissue; M, muscle; HE, hyperproliferative epidermis; G, granulation tissue; Es, eschar (A. Paller, Department of Dermatology, Northwestern University, unpublished data). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound