Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity - PubMed (original) (raw)
Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity
T R Kyriakides et al. Proc Natl Acad Sci U S A. 1999.
Abstract
Disruption of the thrombospondin 2 gene (Thbs2) in mice results in a complex phenotype characterized chiefly by abnormalities in fibroblasts, connective tissues, and blood vessels. Consideration of this phenotype suggested to us that the foreign body reaction (FBR) might be altered in thrombospondin 2 (TSP2)-null mice. To investigate the participation of TSP2 in the FBR, polydimethylsiloxane (PDMS) and oxidized PDMS (ox-PDMS) disks were implanted in TSP2-null and control mice. Growth of TSP2-null and control skin fibroblasts in vitro also was evaluated on both types of disks. Normal fibroblasts grew as a monolayer on both surfaces, but attachment of the cells to ox-PDMS was weak and sensitive to movement. TSP2-null fibroblasts grew as aggregates on both surfaces, and their attachment was further compromised on ox-PDMS. After a 4-week implantation period, both types of PDMS elicited a similar FBR with a collagenous capsule in both TSP2-null and control mice. However, strikingly, the collagenous capsule that formed in TSP2-null mice was highly vascularized and thicker than that formed in normal mice. In addition, abnormally shaped collagen fibers were observed in capsules from mutant mice. These observations indicate that the presence or absence of an extracellular matrix component, TSP2, can influence the nature of the FBR, in particular its vascularity. The expression of TSP2 therefore could represent a molecular target for local inhibitory measures when vascularization of the tissue surrounding an implanted device is desired.
Figures
Figure 1
Characterization of samples by ESCA. (A) Elemental composition of the surfaces of unmodified PDMS and oxygen plasma-treated PDMS (ox-PDMS). (B) Results from the high-resolution Si2p and C1s spectra (n = 3). The % of peak area is the ratio of the area under each of the deconvoluted peaks to the total area under the curve of the element. The error bars indicate SD.
Figure 2
Mouse skin fibroblasts cultured on silicone rubber disks for 48 h. Control (A and C) and TSP2-null fibroblasts (B and D) were plated on PDMS (A and B) and ox-PDMS (C and D). Cells were visualized by staining of their actin cytoskeleton with phalloidin (orange) and their nuclei with 4′,6′-diamidino-2-phenylindole (DAPI) (blue). Control fibroblasts formed a confluent overlapping monolayer on PDMS (A). On ox-PDMS, the monolayer was loosely attached and was disrupted and reassembled into aggregates during the manipulations associated with culture (C). TSP2-null fibroblasts failed to form a monolayer on PDMS (B) or on ox-PDMS (D) but were associated in aggregates. On ox-PDMS the cellular aggregates tended to slide on the biomaterial surface with movement of the culture medium. (Bar = 50 μm for A–D.)
Figure 3
FBR to implanted PDMS disks. Six-millimeter disks were implanted in control (A and C) and TSP2-null mice (B and D) and were removed 4 weeks later. Sections were stained with hematoxylin and eosin (A and B) or Verhoeff-van Gieson stain (C and D). Both treatments stain nuclei dark (blue) and cytoplasm and collagen fibers (pink). Capsules forming around the silicone disks were thicker and more highly vascularized (arrowheads) in TSP2-null mice (B). Collagen fibers in the capsules of control mice appeared dense, parallel, and organized (C). Collagen fibers in the capsules from TSP2-null mice appeared irregular in shape (arrowheads) and were less organized with respect to the implant surface (D). (Bars: A and B = 50 μm; C and D = 50 μm.)
Figure 4
Immunohistochemical localization of TSP2. TSP2 is present within the foreign body capsules of control animals (A and B) and is localized to giant cells on the implant-capsule interface (large arrows). TSP2 is also present in the cells and matrix of the capsule (A and B), with the cells staining more intensely (B, small arrows). The loose reticular layer that surrounds the capsule contains fibroblast-like cells that are also positive for TSP2 (A and B, arrowheads). The presence of TSP2 within the fibers of the reticulum is not obvious. The foreign body capsule is thicker on the side of the implant facing the dermis (A and C) than on the side facing the body wall (B and D). TSP2 is absent from the foreign body capsules of TSP2-null mice (C and D), which serve as a negative control. (Bar = 50 μm for A–D.)
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