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Extracellular Matrix and Actin Cytoskeleton - the Control Unit of Interstitial Fluid Volume
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Kristofer Rubin)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The regulation of fluid (water) volume in the body is crucial for tissue homeostasis. The interstitial fluid, which comprises almost 20% of the body fluid, is stored in the loose connective tissue and its volume is actively regulated by components of this tissue. The loose connective tissue provides a path for fluid flow from capillaries to the tissue and lymphatics. This fluid is partially stored in the interstitium and the remainder is directed to the lymphatics. The fibroblasts in the loose connective tissue actively compact the fibrous extracellular matrix (ECM) through mechanotransduction via integrins. This in turn, maintains the interstitial fluid pressure and keeps the ground substance underhydrated. The interstitial fluid pressure is part of the forces that regulate the efflux of fluid from capillaries and keep the ground substance underhydrated. The underhydrated ground substance has a potential to take up fluid 3-fold the plasma volume. Therefore, the active contraction of the ECM via fibroblasts is crucial to prevent the risk of evacuation of fluid from capillaries. During pathologies, such as inflammation and carcinogenesis, the interstitial fluid pressure and hence the interstitial fluid volume is altered.

The results presented in this thesis show that the signaling events downstream of αVβ3 integrin, collagen-binding β1 integrins, and platelet-derived growth factor receptor β, that induce cell-mediated matrix contraction, included paired function of PI3K and PLCγ, cofilin activation, actin turnover, and generation of actomyosin forces. Furthermore, the results highlight new potential roles for fibrin and αVβ3 integrins, for instance during clearance of edema. Notably, fibrin extravasation at inflammatory sites induced αVβ3 integrin-dependent matrix contraction, leading to normalization of the altered interstitial fluid volume. It also reprograms the expression of ECM-related genes and hence induces ECM turnover. Taken together, these results provide further insight into the regulatory mechanism through which the loose connective tissue actively regulates the interstitial fluid volume.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 971
Keyword [en]
Collagen, fibrin, integrins, PDGF-BB, gel contraction, fluid homeostasis, interstitial fluid pressure
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-217027ISBN: 978-91-554-8865-9 (print)OAI: oai:DiVA.org:uu-217027DiVA: diva2:691651
Public defence
2014-03-14, A1:111a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-02-20 Created: 2014-01-28 Last updated: 2014-04-29
List of papers
1. Opposite effects of PDGF-BB and prostaglandin E(1) on cell-motility related processes are paralleled by modifications of distinct actin-binding proteins
Open this publication in new window or tab >>Opposite effects of PDGF-BB and prostaglandin E(1) on cell-motility related processes are paralleled by modifications of distinct actin-binding proteins
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2009 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, no 10, 1745-1758 p.Article in journal (Refereed) Published
Abstract [en]

Prostaglandin E(1) (PGE(1)) lowers dermal interstitial fluid pressure (IFP) in vivo and inhibits fibroblast-mediated collagen gel contraction in vitro. PDGF-BB, in contrast, stimulates contraction and normalizes IFP lowered as a result of anaphylaxis. Human diploid AG1518 fibroblasts expressed EP2, EP3 and IP prostaglandin receptors. The inhibitory effect of PGE(1) on contraction depended on cAMP. Short-term stimulation with PDGF-BB transiently induced formation of actin-containing membrane and circular ruffles and breakdown of stress fibers. PGE(1) had no effect on stress fibers nor did it modulate the effects of PDGF-BB. PGE(1) alone or in combination with PDGF-BB inhibited initial adhesion and spreading to collagen. PDGF-BB had no effect on adhesion but stimulated cell spreading. Two-dimensional gel electrophoresis and MALDI TOF analyses of SDS/Triton X-100-soluble proteins revealed changes in migration pattern of actin-binding proteins. Interestingly, PDGF-BB and PGE(1) affected both similar and different sets of actin-binding proteins. PDGF-BB and PGE(1) did not trans-modulate their respective effects on actin-binding proteins, cytoskeletal organization or initial adhesion. Our data show that PDGF-BB stimulates actin cytoskeleton dynamics, whereas PGE(1) inhibits processes dependent on cytoskeletal motor functions. We suggest that these different activities may partly explain the contrasting effects of PGE(1) and PDGF-BB on contraction and IFP.

Keyword
Caldesmon, Collagen gel contraction, Cytoskeleton, Extracellular matrix, ERK, Fibroblast, Interstitial fluid pressure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102346 (URN)10.1016/j.yexcr.2009.02.005 (DOI)000266281000011 ()19233168 (PubMedID)
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-11-10Bibliographically approved
2. Signaling pathways involved in both integrin- and PDGF-derived collagen gel contraction
Open this publication in new window or tab >>Signaling pathways involved in both integrin- and PDGF-derived collagen gel contraction
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-217023 (URN)
Available from: 2014-01-28 Created: 2014-01-28 Last updated: 2014-04-29
3. Fibrin binds to collagen and provides a bridge for alpha V beta 3 integrin-dependent contraction of collagen gels
Open this publication in new window or tab >>Fibrin binds to collagen and provides a bridge for alpha V beta 3 integrin-dependent contraction of collagen gels
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2014 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 462, no P1, 113-123 p.Article in journal (Refereed) Published
Abstract [en]

The functional significance of fibrin deposits typically seen in inflammatory lesions, carcinomas and in healing wounds is not fully understood. In the present study, we demonstrate that fibrinogen/fibrin specifically bound to native Col I (collagen type I) and used the Col I fibre network as a base to provide a functional interface matrix that connects cells to the Col I fibres through alpha V beta 3 integrins. This allowed murine myoblast C2C12 cells to contract the collagenous composite gel via alpha V beta 3 integrin. We show that fibrinogen specifically bound to immobilized native Col I at the site known to bind matrix metalloproteinase-1, discoidin domain receptor-2 and fibronectin, and that binding had no effect on Col I fibrillation. A specific competitive inhibitor blocking the Col-I-binding site for fibrinogen abolished the organization of fibrin into discernable fibrils, as well as the C2C12-mediated contraction of Col I gels. Our data show that fibrin can function as a linkage protein between Col I fibres and cells, and suggest that fibrin at inflammatory sites indirectly connects alpha V beta 3 integrins to Col I fibres and thereby promotes cell-mediated contraction of collagenous tissue structures.

National Category
Medical and Health Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-217025 (URN)10.1042/BJ20140201 (DOI)000340218100010 ()
Funder
Swedish Cancer Society, 2010/720Swedish Research Council, 521-2011-2625
Available from: 2014-01-28 Created: 2014-01-28 Last updated: 2017-12-06Bibliographically approved
4. ECM stiffness modulates aVb3 integrin-directed gene expression of ECM-proteins
Open this publication in new window or tab >>ECM stiffness modulates aVb3 integrin-directed gene expression of ECM-proteins
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-217026 (URN)
Available from: 2014-01-28 Created: 2014-01-28 Last updated: 2014-04-29

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Reyhani, Vahid

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