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.

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

“…To conclusively demonstrate that retention of cochlin in lymphoid conduits depended on collagen VII, we systemically ablated Col7a1 expression in a tamoxifen-inducible Col7a1 knockout mouse (1). In accordance with the previously established half-life of collagen VII (38), tamoxifen treatment led to a significant loss of collagen VII in skin and spleen after >10 wk (Fig.…”

“…For the studies, samples from human individuals with molecularly confirmed severe generalized recessive RDEB were used, as well as two genetic mouse models, the collagen VII hypomorphic RDEB mouse and a tamoxifen-inducible Col7a1 knockout mouse (1). The RDEB mouse shows all major signs of severe RDEB (25), and the tamoxifen-inducible Col7a1 knockout mouse allows targeted ablation of Col7a1 expression in time and space (1). RDEB is a progressive disease.…”

“…The mice were kept in a pathogen-free facility at the University of Freiburg with ad libitum access to food and water; RDEB mice were also provided a soft food diet (1). Mixed male and female mice were used for the analyses.…”

“…It is particularly useful since, in contrast to human patients, the mice do not develop large wounds due to stabilization of skin by the fur (1,23) (Fig. 1).…”

“…collagen VII | innate immunity | bacteria | recessive dystrophic epidermolysis bullosa | cochlin R ecessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder caused by mutations in the COL7A1 gene encoding collagen VII, a large extracellular matrix (ECM) protein and the main component of anchoring fibrils, which ensure skin integrity (1). Mechanically induced skin blistering, painful wounds, and healing with scarring severely impede the quality of life of the affected individuals (2,3).…”