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Fibrin fragment E stimulates fibroblast migration and enhances TGF-β induced myofibroblast differentiation through an integrin β3-dependent activation of Toll-like receptor 4
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Gerwins)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-196882OAI: oai:DiVA.org:uu-196882DiVA: diva2:611067
Available from: 2013-03-14 Created: 2013-03-14 Last updated: 2013-08-30
In thesis
1. Myofibroblasts and the Vascular Endothelium: Impact of Fibrin Degradation Products and miRNA on Vascular Motility and Function
Open this publication in new window or tab >>Myofibroblasts and the Vascular Endothelium: Impact of Fibrin Degradation Products and miRNA on Vascular Motility and Function
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis is the formation of new blood vessels from pre-existing vasculature and is important during development as well as wound healing and tissue remodeling. Angiogenesis also occurs during pathological conditions such as diabetic retinopathy and cancer. This thesis is centered on the biology of endothelial cells, lining the blood vessels, and myofibroblasts, important for wound healing.

We investigated an endothelial cell specific gene, ExoC3l2, and its role in VEGFR2 signaling and migration. EXOC3L2 co-localize with members of the exocyst complex, involved in vesicular transport, as well as VEGFR2. Reducing the level of EXOC3L2 in microvascular endothelial cells results in reduced VEGFR2 signaling and subsequently reduced chemotactic response to VEGF-A.

MicroRNA (miRNA) have been shown to be regulators of gene transcription and cell type specific miRNAs have been identified. We investigated two miRNAs, miR-145 and miR-24. miR-145 is expressed in pericytes and fibroblasts but was shown to regulate fli1, an endothelial transcription factor. miR-145 overexpression reduced chemotaxis in both fibroblasts and endothelial cells, as did suppression of the endogenous miR-145 level in fibroblasts.

miR-24 in contrast is expressed by endothelial cells and are able to target Ndst1, important for heparan sulfate (HS) sulfation. Sulfation of HS is important for many processes, amongst them growth factor signaling. Overexpression of miR-24 resulted in lower sulfation of HS chains, decreasing the ability of HS to interact with VEGF-A. Overexpressing miR-24 resulted in disturbed chemotaxis, similar to suppressing Ndst1 using siRNA.

Myofibroblast recruitment is an important step in wound healing. The myofibroblasts contract the wound, synthesize new extracellular matrix and contribute to revascularization by looping angiogenesis. Maturation from resting fibroblast to myofibroblast is dependent on TGF-β. We found that fibrin fragment E (FnE), a degradation product of fibrin, potentiated the response of fibroblasts to TGF-β thus enhancing TGF-β-induced myofibroblast differentiation. FnE was also found to influence the migration of fibroblasts. These responses are dependent on integrins and toll-like receptors.

These findings may serve to further increase the understanding of angiogenesis and wound healing to develop new therapies against pathological conditions.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 878
Keyword
Angiogenesis, Vascular biology, Chemotaxis, Endothelial cell, Myofibroblast, Wound healing, miRNA, Heparan sulfate
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-196884 (URN)978-91-554-8622-8 (ISBN)
Public defence
2013-05-03, A1:111a, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-04-11 Created: 2013-03-14 Last updated: 2013-08-30Bibliographically approved

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Fredlund Fuchs, Peder

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