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Integrin α1β1 is Involved in the Differentiation into Myofibroblasts in Adult Reactive Tissues in vivo
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
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2009 (English)In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 13, no 9b, 3449-3462 p.Article in journal (Refereed) Published
Abstract [en]

Connective tissue cell activation is of importance during reactive conditions such as solid tumor growth, wound healing and pannus formation in rheumatoid arthritis. Here we have compared connective tissue cells of mesenchymal origin in human tissues from these conditions and their normal counterparts using a panel of cell type-specific markers. In particular, we investigated variations of integrin expression among connective tissue cell phenotypes. Connective tissue cell populations were defined based on their association with the microvasculature and their expression of activation markers. The phenotype of these cells varied according to the type of pathological connective tissue examined. Our morphological data from human tissues suggested that the alpha1beta1 integrin, a collagen/laminin receptor, is involved in the differentiation of precursor cells to myofibroblasts. In order to mechanistically investigate this hypothesis we employed experimental models for carcinoma growth and wound healing utilizing alpha1 integrin deficient mice. The data confirmed that the alpha1beta1 integrin is of importance for the differentiation of mesenchymal cells to myofibroblasts but also for neovascularization and connective tissue organization and emphasizes the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumor growth.

Place, publisher, year, edition, pages
2009. Vol. 13, no 9b, 3449-3462 p.
Keyword [en]
Adenocarcinoma rheumatoid arthritis, Integrin connective tissue, Matrigel, Myofibroblast, Pericyte
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-119722DOI: 10.1111/j.1582-4934.2008.00638.xISI: 000274179300044PubMedID: 19397781OAI: oai:DiVA.org:uu-119722DiVA: diva2:300741
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Studies of Stroma Formation and Regulation in Human Pathological Conditions and in Experimental in vivo Models
Open this publication in new window or tab >>Studies of Stroma Formation and Regulation in Human Pathological Conditions and in Experimental in vivo Models
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibrosis is a sequel of chronic inflammation and is defined as an excessive deposition of collagen that ultimately leads to organ dysfunction. To date there are no effective treatments for fibrosis. The main cell type involved in collagen deposition and organization is the myofibroblast.

In the first study we examined how myofibroblasts differentiate in human fibrotic conditions and in experimental animal models. Human tissues were stained with antibodies that recognize integrin receptors and in addition we also stained for α-SMA, a myofibroblast marker. We found a co-localization between these two markers in stromal cells and hypothesized that integrin α1 is important for the acquisition of the myofibroblast phenotype. To tests this hypothesis we used knockout animals for this integrin subunit. These animals showed a reduction of α-SMA positive fibroblasts, indicating that the α1 integrin subunit is required for proper myofibroblast differentiation.

In the second study we used a neuroblastoma tumor model to study tumour growth when a drug targeting the synthesis of cellular NAD was administered. In treated animals an expansion of the nonvascular stroma was observed compared to controls. Normalization of the vasculature was observed in treated tumors together with a decrease in hypoxia. Moreover, this was followed by a decrease in stromal PDGF-B and VEGF expression, suggesting a deactivation of the stroma.

In the third study the effects of over-expression of the two pro-fibrotic growth factors TGF-β and PDGF-B in skin was evaluated. We observed that both growth factors induced fibrosis. Over time, a decrease in blood vessel density was observed in both treatment groups. Both factors also stimulated an expansion of the connective tissue cell population originating from the microvascular pericyte, but the phenotype of these cells differed in the different treatments with regards to expression of markers. Furthermore, in tissue over-expressing PDGF-B but not TGF-β, the fibrotic process was partially reversible.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 541
Keyword
Fibrosis, Tumor Stroma, Myofibroblast, Pericyte, Angiogenesis, Inflammation, adenovirus
National Category
Cell and Molecular Biology Cell and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-120688 (URN)978-91-554-7754-7 (ISBN)
Public defence
2010-04-28, B22, Uppsala biomedicinska centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2010-04-07 Created: 2010-03-15 Last updated: 2010-04-07
2. The Role of Microvascular Pericytes in the Generation of Pro-fibrotic Connective Tissue Cells: Investigations in vitro and in Reactive Tissues in vivo
Open this publication in new window or tab >>The Role of Microvascular Pericytes in the Generation of Pro-fibrotic Connective Tissue Cells: Investigations in vitro and in Reactive Tissues in vivo
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pericytes are cells of mesenchymal origin located on the abluminal side, juxtapositioned to the endothelial cells in capillaries, venules and small arterioles. They are important for maintaining vessel integrity in resting tissues as well as the formation and stabilization of new vessels. They have been suggested to function as mesenchymal stem cells thereby contributing to the connective tissue cell population in reactive tissues. In this thesis the role of pericytes as progenitors for fibroblasts was further defined both in vitro and in vivo. In the first study connective tissue cells of mesenchymal origin were investigated based on their marker expression and relation to the microvasculature. The expression of alpha smooth muscle actin (α-SMA), a marker for myofibroblasts, was compared to the expression of certain integrins in three reactive conditions in human tissues. There was a co-localization of α-SMA and α1β1 integrins, indicating that α1 integrin was important for acquiring the α-SMA myofibroblast phenotype. To further investigate this, two animal models for carcinoma growth and wound healing using α1 deficient mice were employed. Reduction/lack of α-SMA expressing myofibroblasts substantiated or findings in human tissues, strengthening the hypothesis that the α1 integrin is important for the differentiation of α-SMA expressing myofibroblasts. In study two the effects of the HDAC inhibitor valproic acid (VPA) on pericyte function in vitro was investigated. This revealed that VPA had an inhibitory effect on pericyte proliferation, migration and differentiation into collagen type I producing fibroblasts. In addition qPCR array studies on angiogenesis related gene expression identified an up-regulation of genes involved in vessel stabilization in VPA treated pericytes. This suggests that VPA promotes a pericyte phenotype favoring vessel stability. In study three the differentiation from early mesenchymal stem cell like pericyte to fully differentiated fibroblast was further defined by flow cytometry marker analysis. By isolating pericytes from human placenta with a phenotype resembling the in vivo phenotype the differentiation pathway could be defined in five consecutive steps. The five steps were defined by their marker expression and their ability to give rise to the other cell populations in the differentiation lineage, as well as their slow cycling characteristics. A better understanding of how connective tissue cells are derived in fibrotic conditions may be beneficial in trying to modulate the outcome of the healing process towards optimal tissue regeneration with minimal fibrosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 38 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 618
Keyword
pericyte fibroblast differentiation fibrosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Microbiology in the medical area Cell and Molecular Biology
Research subject
Medical Biochemistry; Cell Research; Microbiology
Identifiers
urn:nbn:se:uu:diva-132611 (URN)978-91-554-7938-1 (ISBN)
Public defence
2010-12-02, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-11-11 Created: 2010-10-22 Last updated: 2011-01-13Bibliographically approved

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Gerdin, BengtRubin, KristoferSundberg, Christian

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