Collagen VII plays a dual role in wound healing
Alexander Nyström, … , Johannes S. Kern, Leena Bruckner-Tuderman
Alexander Nyström, … , Johannes S. Kern, Leena Bruckner-Tuderman
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3498-3509. https://doi.org/10.1172/JCI68127.
View: Text | PDF
Research Article Dermatology Article has an altmetric score of 20

Collagen VII plays a dual role in wound healing

Abstract

Although a host of intracellular signals is known to contribute to wound healing, the role of the cell microenvironment in tissue repair remains elusive. Here we employed 2 different mouse models of genetic skin fragility to assess the role of the basement membrane protein collagen VII (COL7A1) in wound healing. COL7A1 secures the attachment of the epidermis to the dermis, and its mutations cause a human skin fragility disorder coined recessive dystrophic epidermolysis bullosa (RDEB) that is associated with a constant wound burden. We show that COL7A1 is instrumental for skin wound closure by 2 interconnected mechanisms. First, COL7A1 was required for re-epithelialization through organization of laminin-332 at the dermal-epidermal junction. Its loss perturbs laminin-332 organization during wound healing, which in turn abrogates strictly polarized expression of integrin α6β4 in basal keratinocytes and negatively impacts the laminin-332/integrin α6β4 signaling axis guiding keratinocyte migration. Second, COL7A1 supported dermal fibroblast migration and regulates their cytokine production in the granulation tissue. These findings, which were validated in human wounds, identify COL7A1 as a critical player in physiological wound healing in humans and mice and may facilitate development of therapeutic strategies not only for RDEB, but also for other chronic wounds.

Authors

Alexander Nyström, Daniela Velati, Venugopal R. Mittapalli, Anja Fritsch, Johannes S. Kern, Leena Bruckner-Tuderman

×

Figure 6

Granulation tissue maturation and clearance of inflammatory cells are delayed in Col7a1-hypomorphic wounds.

Options: View larger image (or click on image) Download as PowerPoint
Granulation tissue maturation and clearance of inflammatory cells are de...
(A) α-SMA staining (red) showed few myofibroblasts at the wound edge at day 3 in both wild-type and Col7a1-hypomorphic mice. At day 7, myofibroblasts were abundant in the middle of the wild-type wound, but remained in the periphery of the Col7a1-hypomorphic wound. Dashed outlines denote the dense myofibroblast regions. Myofibroblast organization in the day 9 Col7a1-hypomorphic wound was similar to that of 7-day wild-type wounds, with myofibroblasts localized in the upper central part of the granulation tissue. At day 16 after wounding, most myofibroblasts had disappeared in both mice. Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (B) CD11b staining (green) revealed protracted clearance of inflammatory cells in Col7a1-hypomophic wounds. At day 3, inflammatory cells were at the wound edge in both wild-type and Col7a1-hypomorphic mice. At day 7, inflammatory cells were mainly seen in the middle of the wound in both mice. At day 16, CD11b-positive cells were cleared from the wound area in wild-type mice, but not in Col7a1-hypomorphic mice. Nuclei were stained with DAPI (blue). Scale bar: 100 μm. See Supplemental Figure 12 for quantification of granulation tissue changes.