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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3681-3681
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  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.
 Charles W. Francis
University of Rochester
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W. Matsui, C. A. Huff, Q. Wang, M. T. Malehorn, J. Barber, Y. Tanhehco, B. D. Smith, C. I. Civin, and R. J. Jones
Characterization of clonogenic multiple myeloma cells
Blood,
March 15, 2004;
103(6):
2332 - 2336.
[Abstract]
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