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.
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Research Article Dermatology

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

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Figure 8

Human RDEB and other chronic wounds display similar molecular alterations.

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Human RDEB and other chronic wounds display similar molecular alteration...
Wound biopsies were obtained from fresh wounds 3 days after primary excision (Acute wound), from the wound margins of nonhealing chronic venous ulcers, and from wounds of RDEB patients. (A) Wounds were stained for laminin-332 (red) and integrin α6 (green) or for COL7A1 (red). Yellow arrowheads denote the end of the epithelial front in the acute wound. For chronic and RDEB wounds, the epithelial front in the wound margin is shown. Acute wounds showed linear deposition of laminin-332 and regular, primarily basal, expression of integrin α6, whereas in chronic and RDEB wounds, laminin-332 deposition was irregular and integrin α6 expression suprabasal (white arrows). Importantly, in acute wounds, COL7A1 was distinctly present under the healing epidermis, whereas it was irregular and drastically reduced in chronic wounds. Nuclei were visualized with DAPI (blue). Scale bar: 50 μm. (B) Epidermal tongues in wound margins stained for phospho-JNK (green) or phospho-STAT3 (green). Nuclei were counterstained with DAPI (blue). Red lines denote the epidermal-dermal interface. In acute wounds, phospho-JNK and phospho-STAT3 staining was weak and mainly seen in basal keratinocytes, whereas both chronic and RDEB wounds showed strong phospho-JNK and phospho-STAT3 staining in suprabasal keratinocytes. Scale bar: 50 μm.