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Functional overlap between two classes of matrix-degrading proteases in wound healing.

ABSTRACT: Retarded wound healing was found in mice deficient in the serine protease precursor plasminogen, as well as in wild-type mice treated with the metalloprotease inhibitor galardin, but in both cases wound closure was ultimately completed in all mice within 60 days. The expression of several matrix metalloproteases in keratinocytes migrating to cover the wound was strongly enhanced by galardin treatment. However, when plasminogen-deficient mice were treated with galardin, healing was completely arrested and wound closure was not seen during an observation period of 100 days, demonstrating that protease activity is essential for skin wound healing. The requirement for both plasminogen deficiency and metalloprotease inhibition for complete inhibition of the healing process indicates that there is a functional overlap between the two classes of matrix-degrading proteases, probably in the dissection of the fibrin-rich provisional matrix by migrating keratinocytes. Each class alone is capable of maintaining sufficient keratinocyte migration to regenerate the epidermal surface, although this function would normally be performed by both classes acting in parallel. Since there are strong similarities between the proteolytic mechanisms in wound healing and cancer invasion, these results predict that complete arrest of this latter process in therapeutic settings will require the use of inhibitors of both classes of proteases.

SUBMITTER: Lund LR

PROVIDER: S-EPMC1171538 | biostudies-other | 1999 Sep

REPOSITORIES: biostudies-other

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Functional overlap between two classes of matrix-degrading proteases in wound healing.

Lund L R LR Romer J J Bugge T H TH Nielsen B S BS Frandsen T L TL Degen J L JL Stephens R W RW Danø K K

The EMBO journal 19990901 17

Retarded wound healing was found in mice deficient in the serine protease precursor plasminogen, as well as in wild-type mice treated with the metalloprotease inhibitor galardin, but in both cases wound closure was ultimately completed in all mice within 60 days. The expression of several matrix metalloproteases in keratinocytes migrating to cover the wound was strongly enhanced by galardin treatment. However, when plasminogen-deficient mice were treated with galardin, healing was completely arr ...[more]

PMID: 10469644

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Project description:The increasing economic burden of wound healing in healthcare systems requires the development of functional therapies. Xenografts with preserved extracellular matrix (ECM) structure and biofunctional components overcome major limitations of autografts and allografts (e.g. availability) and artificial biomaterials (e.g. foreign body response). Although porcine mesothelium is extensively used in clinical practice, it is under-investigated for wound healing applications. Herein, we compared the biochemical and biological properties of the only two commercially available porcine mesothelium grafts (Meso Biomatrix® and Puracol® Ultra ECM) to traditionally used wound healing grafts (Endoform™, ovine forestomach and MatriStem®, porcine urinary bladder) and biomaterials (Promogran™, collagen/oxidized regenerated cellulose). The Endoform™ and the Puracol® Ultra ECM showed the highest (p<0.05) soluble collagen and elastin content. The MatriStem® had the highest (p<0.05) basic fibroblast growth factor (FGFb) content, whereas the Meso Biomatrix® had the highest (p<0.05) transforming growth factor beta-1 (TGF-β1) and vascular endothelial growth factor (VEGF) content. All materials showed tissue-specific structure and composition. The Endoform™ and the Meso Biomatrix® had some nuclei residual matter. All tissue grafts showed similar (p>0.05) response to enzymatic degradation, whereas the Promogran™ was not completely degraded by matrix metalloproteinase (MMP)-8 and was completely degraded by elastase. The Promogran™ showed the highest (p<0.05) permeability to bacterial infiltration. The Promogran™ showed by far the lowest dermal fibroblast and THP-1 attachment and growth. All tested materials showed significantly lower (p<0.05) tumor necrosis factor-alpha (TNF-α) expression than the lipopolysaccharides group. The MatriStem® and the Puracol® Ultra ECM promoted the highest (p<0.05) number of micro-vessel formation, whereas the Promogran™ the lowest (p<0.05). Collectively, these data confer that porcine mesothelium has the potential to be used as a wound healing material, considering its composition, resistance to enzymatic degradation, cytocompatibility, and angiogenic potential.

Project description:BackgroundStem cell therapies represent a promising tool in regenerative medicine. Considering the drawbacks of direct stem cell injections (e.g. poor cell localisation), extracellular matrix-based biomaterials (e.g. scaffolds and tissue grafts), due to their compositional biofunctionality and cytocompatibility, are under investigation as potential stem cell carriers.MethodsThe present study assessed the potential of three commercially available extracellular matrix-based biomaterials [a collagen/glycosaminoglycan scaffold (Integra™ Matrix Wound Dressing), a decellularised porcine peritoneum (XenoMEM™) and a porcine urinary bladder (MatriStem™)] as human adipose-derived stem cell delivery vehicles.ResultsBoth tissue grafts induced significantly (p < 0.01) higher human adipose-derived stem cell proliferation in vitro over the collagen scaffold, especially when the cells were seeded on the basement membrane side. Human adipose-derived stem cell phenotype and trilineage differentiation potential was preserved in all biomaterials. In a splinted wound healing nude mouse model, in comparison to sham, biomaterials alone and cells alone groups, all biomaterials seeded with human adipose-derived stem cells showed a moderate improvement of wound closure, a significantly (p < 0.05) lower wound gap and scar index and a significantly (p < 0.05) higher proportion of mature collagen deposition and angiogenesis (the highest, p < 0.01, was observed for the cell loaded at the basement membrane XenoMEM™ group). All cell-loaded biomaterial groups retained more cells at the implantation side than the direct injection group, even though they were loaded with half of the cells than the cell injection group.ConclusionsThis study further advocates the use of extracellular matrix-based biomaterials (in particular porcine peritoneum) as human adipose-derived stem cell delivery vehicles. Comparative analysis of a collagen scaffold (Integra™ Matrix Wound Dressing) and two tissue grafts [decellularised porcine peritoneum (XenoMEM™) and porcine urinary bladder (MatriStem™)] as human adipose-derived stem cells carriers.

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Functional overlap between two classes of matrix-degrading proteases in wound healing.

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Functional overlap between two classes of matrix-degrading proteases in wound healing.

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