Wound-healing defects in mice lacking fibrinogen

Abstract

In addition to its key role in the control of blood loss following injury, fibrin(ogen) has been proposed to play an important role in tissue repair by providing an initial matrix that can stabilize wound fields and support local cell proliferation and migration. To test directly these concepts, the effect of fibrinogen deficiency on cutaneous tissue repair in mice was investigated using incisional and excisional wounds. The time required to overtly heal wounds was similar in fibrinogen-deficient and control mice, but histologic evaluation revealed distinct differences in the repair process, including an altered pattern of epithelial cell migration and increased epithelial hyperplasia. Furthermore, granulation tissue in fibrinogen-deficient mice failed to adequately close the wound gap, resulting in persistent open wounds or partially covered sinus tracts. The tensile strength of these wounds was also reduced compared with control mice. The most profound defect in wound tissue organization was observed in fibrinogen-deficient mice following the subcutaneous implantation of a porous tubing chamber. Cells migrated into the wall of the implants at a similar rate as control mice, but cells from fibrinogen-deficient animals were unable to efficiently organize and migrate into wound fluid-filled dead space within the center of the implants. These studies show that re-epithelialization, granulation tissue formation, including the establishment of neovasculature, and the formation of fibrotic scar tissue can proceed in the absence of fibrin(ogen) and all of its proteolytic derivatives. However, fibrin (ogen) is important for appropriate cellular migration and organization within wound fields and in initially establishing wound strength and stability. (Blood. 2001;97:3691-3698)

Matrix-fibrinogen enhances wound closure by increasing both cell proliferation and migration

“…Although wound repair ultimately proceeds in a relatively normal manner in the absence of fibrin (ogen) or its biologically active fragments derived from proteolysis, the data show that fibrin(ogen) is important for appropriately directed cellular migration in a temporal and spatial manner within the wound space and to establish wound strength and stability. 52 We show in this report that matrix-FBG enhances both wound closure and cell proliferation to significantly shorten the time to wound closure in a dermal fibroblast model of tissue injury. Specific cell-binding domains on matrix-FBG are required to support accelerated wound closure.…”

“…During cutaneous wound healing, the FBGdeficient mice show an abnormal pattern of tissue repair, including misguided and hypertrophied epithelium, enhanced collagen deposition, delayed wound closure, and reduced wound tensile strength. 52 The most profound defect in tissue organization found in FBGdeficient mice is the inability of cells to efficiently organize and migrate into the wound space. Although wound repair ultimately proceeds in a relatively normal manner in the absence of fibrin (ogen) or its biologically active fragments derived from proteolysis, the data show that fibrin(ogen) is important for appropriately directed cellular migration in a temporal and spatial manner within the wound space and to establish wound strength and stability.…”

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

“…These findings do however appear contradictory to the studies showing that fibrinogen-deficient mice are as susceptible to lung fibrosis as wild-type mice after bleomycin administration 60 -62 and are also able to produce granulation tissue and heal full-thickness skin wounds. 63,64 One explanation for this phenomenon is that fibrin(ogen) itself is not essential for collagen accumulation but that its persistence, or that of another component of the fibrin matrix, promotes and prolongs collagen accumulation. In addition, the type of fibrin matrix deposited at sites of tissue damage are likely to vary considerably in terms of composition, degree of crosslinking, mechanical stress, as well as cellularity, and these properties may influence the behavior of fibroblasts and the resultant amount of collagen formed.…”

The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats

“…However, we could not detect any increased mature blood vessel structures upon HIF-1α gene or VEGF protein delivery. Fibrin per se has wound healing properties [47] and it might be possible that fibrin masks the effect of wound revascularization after HIF-1α gene delivery. Nevertheless, the elevated levels of endothelial cells and α-SMA positive cells suggest that the wounds respond with a preliminary angiogenic response to the polymer-DNA condensates without forming increased mature blood vessels structures at the time points of analyzes.…”