Disorganized wound healing in fibrinogen-deficient mice

The dramatic conversion of blood from liquid to solid focused attention for decades on the role of fibrinogen in clot formation. But the cellular interactions of fibrinogen, fibrin, and their many proteolytic derivatives are critical in many physiologic and pathologic procedures. For example, most vascular cells have receptors for fibrinogen, which plays an important role in establishing cell-cell interactions, frequently after receptor activation. In contrast to fibrinogen, vascular cells are rarely exposed to fibrin, which is formed primarily at sites of injury, thrombosis, inflammation, or malignancy. Fibrin exposure results in dramatic changes in phenotype, frequently including loss of cell-cell contacts, migration, changes in secretion and synthesis of proteins, and angiogenic organization of endothelial cells. These responses are influenced by both the physical characteristics of the fibrin network and also by the exposure of new sites following thrombin cleavage such as the amino terminus of the β chain that interacts with endothelial cell VE-cadherin.

The development of knockout mice deficient in fibrinogen has provided new insights into its physiologic role in these and other processes. Mice lacking fibrinogen have defective hemostasis, but, surprisingly, they can survive, reproduce, and even establish hemostasis after minor surgical procedures. Previous studies using these mice have shown that fibrinogen contributes to metastatic potential, modulates atherogenesis, and affects the intensity of inflammation in arthritis. The report by Drew and colleagues (page 3691) examines wound healing in fibrinogen-deficient (Fib^−/−) mice. Some negative findings were particularly surprising. Fib^−/− mice exhibited little gross difference in would healing except for persistent minor bleeding and slightly delayed re-epithelization. But there were major differences in the details of the healing process. Wounds in Fib^−/− mice had a relative lack of granulation tissue with decreased tensile strength, and the wound tended to gap and fissure. Dramatic alterations were seen in cell migration. Following skin wounding, keratinocytes in controls migrated beneath the eschar from the edges to the center and closed the wound in an ordered process. In Fib^−/− mice this process was disordered with epithelial hyperplasia and cell migration into fissures and sinuses directed away from the wound center. When a porous chamber was implanted into Fib^−/− mice, cells failed to migrate into the dead space in the absence of a fibrin matrix.

The results indicate that fibrin is needed to provide tensile strength for wounds and in directing cell migration, and they raise additional questions concerning the role of fibrinogen and fibrin in healing and inflammation. It will be important to determine how keratinocytes and possibly other epithelial cells recognize fibrin and how it directs their migration. The difference in wound collagen content in Fib^−/− mice suggests a new and important role of fibrin in regulating fibroblast collagen synthesis. The alternative mechanisms that allow eventual complete wound healing in Fib^−/− mice need further investigation. The important role of fibrin(ogen) in directing cellular processes in healing, tumor development, and inflammation raises the possibility of modulating these interactions for therapeutic benefit.