128 Characterization of mice devoid of integrins α1β1, α2β1 and α11β1

Virtually all cells in vertebrates are in contact with one of the 28 collagen types, the most abundant class of proteins in our body. Integrins α1β1, α2β1 and α11β1 are the main collagen receptors mediating these contacts. Ablation of single receptors has revealed multifaceted and non-overlapping functions in cell survival, differentiation, hemostasis, inflammation and angiogenesis. However, the phenotypes of all knockout models were relatively mild. We raised the question whether integrins recognize their binding sites also in aggregated collagens, such as in heterotypic fibrils which contain several collagens (I, III, V, XII) and non-collagen constituents (decorin, matrilin). Here, we generated mice globally lacking the integrins α1β1, α2β1 and α11β1 (triple knockout, tKO). These mice developed normally indicating that integrin mediated direct contacts between cells and collagens are dispensable for development. The histology of tKO skin was inconspicuous in the light microscope. Fibroblasts, normally expressing all 3 integrins, failed to adhere to and migrate on collagen while fibronectin supported both. tKO dermal fibroblasts deposited less collagen I, but more fibronectin than control fibroblasts. Normal fibroblasts plated onto matrices formed by mutant cells spread to smaller size than on control matrices. Therefore, adhesion-related properties are conferred to the extracellular matrix by collagen integrins as well as unrelated matrix receptors. tKO fibroblasts remained smaller even if plated onto control matrices, revealing an additional cell-autonomous effect. Integrins such as α2β1 and α11β1 are required for the orchestration of collagen-rich tissue when challenged, e.g. in tissue repair or during the induction of a fibrosis. We expect that these situations will be altered in tKO mice. In addition, tKO-mice provide a unique model to investigate functions of non-integrin collagen receptors in tissue homeostasis.