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Review
. 2014 Mar 1;3(3):247-263.
doi: 10.1089/wound.2013.0489.

Focal Contact and Hemidesmosomal Proteins in Keratinocyte Migration and Wound Repair

Susan B Hopkinson  1 , Kevin J Hamill  1 , Yvonne Wu  1 , Jessica L Eisenberg  1 , Sho Hiroyasu  1 , Jonathan C R Jones  1
Affiliations
Review

Focal Contact and Hemidesmosomal Proteins in Keratinocyte Migration and Wound Repair

Susan B Hopkinson et al. Adv Wound Care (New Rochelle). .

Abstract

Significance: During wound healing of the skin, keratinocytes should move over while still adhering to their underlying matrix. Thus, mechanistic insights into the wound-healing process require an understanding of the forms and functions of keratinocyte matrix adhesions, specifically focal contacts and hemidesmosomes, and their components. Recent Advances: Although the structure and composition of focal contacts and hemidesmosomes are relatively well defined, the functions of their components are only now being delineated using mouse genetic models and knockdown approaches in cell culture systems. Remarkably, both focal contact and hemidesmosomal proteins appear involved in determining the speed and directional migration of epidermal cells by modulating several signal transduction pathways. Critical Issues: Although many publications are centered on focal contacts, their existence in tissues such as the skin is controversial. Nonetheless, focal contact proteins are central to mechanisms that regulate skin cell motility. Conversely, hemidesmosomes have been identified in intact skin but whether hemidesmosomal components play a positive regulatory function in keratinocyte motility remains debated in the field. Future Directions: Defective wound healing is a developing problem in the aged, hospitalized and diabetic populations. Hence, deriving new insights into the molecular roles of matrix adhesion proteins in wound healing is a prerequisite to the development of novel therapeutics to enhance tissue repair and regeneration.

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Figures

None
Jonathan C.R. Jones, PhD
<b>Figure 1.</b>
Figure 1.
A schematic of the edge of a wound-healing epidermis. On the left, a keratinocyte in an unwounded region adheres to the laminin-332 (LM332) in the basement membrane (BM) in part through a keratin-associated hemidesmosome (HD) and possibly, an actin-interacting focal contact (FC). The HD is targeted by kinases and proteases (arrow) in cells at the wound margin (middle cell). Cells that leave the BM move over a provisional matrix composed of fibronectin (depicted as fibrils) and laminin-332. Focal contact and hemidesmosomal integrins interact with this matrix and likely regulated the directed migration of the motile keratinocytes. The box indicates the key for α3β1 and α6β4 integrin heterodimers.
<b>Figure 2.</b>
Figure 2.
Schematics of the protein components of the focal contact (left) and hemidesmosome (right).
<b>Figure 3.</b>
Figure 3.
Immortalized human keratinocytes were allowed to attain confluence in vitro and were then scratched wounded. At 6 h after wounding, the cells were prepared for confocal immunofluorescence using antibodies against β4 integrin (A). Cells at the wound edge have begun to move onto the wound site. White arrows indicate β4 integrin staining along the leading lamellipodia of cells at the wound margin. These same areas are marked by arrows in the phase image of the cells in (B). Scale bar, 20 μm.
<b>Figure 4.</b>
Figure 4.
Immortalized human keratinocytes maintained at sub-confluence in vitro were prepared for triple label immunofluorescence using antibodies against α6 integrin, laminin-332, and paxillin as indicated. The merge of the three images indicates that α6 integrin-rich hemidesmosome protein complexes co-distribute with laminin-332, while paxillin focal contacts localize at the very edge of the cells and fail to show clear co-localization with laminin-332. The phase image shows the cell outline. Scale bar, 10 μm.
<b>Figure 5.</b>
Figure 5.
The images show the migrating tongue of keratinocytes in an incisional human wound at 30 h after wounding. The cells were moving toward the right [large arrows in (A) and (B) indicate the direction of movement]. (A) The section was prepared for immunofluorescence using antibodies against α3 integrin (red) and BPAG1e (green). The nuclei are stained with DAPI (blue). α3 integrin (red) is predominantly at sites of cell-to-cell contact with no clear co-distribution with BPAG1e (green) located along the advancing wound margin juxtaposed to the wound matrix (arrows). (B) The section was costained with antibodies against β4 integrin (red) and BPAG1e (green). The nuclei are stained with DAPI (blue). Note that β4 integrin and BPAG1e co-distribute as evidenced by the yellow color along the wound margin (arrows). M, matrix of wound bed. These images were presented in Underwood et al. as Figs. 8C and 5C. Scale bar, 10 μm.
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