Universität zu Köln

Kümper, Maike (2022). Role of stromal MMP14 and MMP3 in skin homeostasis. PhD thesis, Universität zu Köln.

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Abstract

The pleiotropic functions of MMP14 were underscored in mice with global deletion which suffered from multiple defects leading to death within three weeks after birth. Cell-type specific deletions of MMP14 enabled further analysis its functions in development and pathology. Mice with constitutive MMP14 deletion in endothelial cells (MMP14EC-/-) developed and bred normal with no obvious phenotype. However, growth and lung metastasis of B16F1 melanoma in MMP14EC-/- mice was reduced. This was accompanied by decreased vascular permeability, likely a consequence of enhanced pericytes coverage, VE-cadherin expression and reduced nitric oxide production resulting from less eNOS expression. These results indicated that endothelial-derived MMP14 may be effective in reducing melanoma metastasis and enhance vessel stabilization. In a second model mice with fibroblast-specific deletion of MMP14 (MMP14Sf-/-) developed a fibrosis-like phenotype, however cutaneous repair was normal in these mice. Protein and RNA analysis of the skin and isolated fibroblasts identified upregulated MMP3 expression in MMP14Sf-/- mice. To address the functional significance for MMP3 in that context, we generated mice with MMP3 deletion in addition to fibroblast-specific loss of MMP14 (MMP3-/-/MMP14Sf-/- mice). These mice resembled the fibrotic phenotype of MMP14Sf-/- mice. In contrast, skin repair showed delayed wound closure and enhanced granulation tissue formation in double deficient mice, accompanied by a myofibroblast phenotype in all knockout mice. In early wound myofibroblast population of the wound tissue was reduced, but persisted longer in later wounds compared to wild type mice. Although we did not find altered TGFβ1 in wound tissue, and isolated skin fibroblasts from all mice genotypes were functionally able to respond to TGFβ1 and to mechanical stimuli, we cannot exclude that in vivo release of ECM-bound TGFβ1 in single and double MMP3-/-/MMP14Sf-/- knockout mice is altered, this needs further investigations. Reduced myofibroblast clearance from later wounds was accompanied by reduced apoptosis in all knockouts. These studies provide new cell type-specific regulatory functions of MMP14 and MMP3 in mediating skin repair through the regulation of myofibroblasts homeostasis in wounds. Defense date: April 20th 2023

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kümper, Maike maike_1991@gmx.net UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-708741
Date:	18 December 2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Medicine > Dermatologie > Klinik und Poliklinik für Dermatologie und Venerologie
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language MMP14 UNSPECIFIED MMP3 UNSPECIFIED Melanoma UNSPECIFIED Angiogenesis UNSPECIFIED Wound healing UNSPECIFIED Myofibroblast UNSPECIFIED
Date of oral exam:	20 April 2023
Referee:	Name Academic Title Baumann, Ulrich Professor Sengle, Gerhard Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70874