uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Phenotypical differences in connective tissue cells emerging from microvascular pericytes in response to over-expression of PDGF-B and TGF-beta in normal skin 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 Medical Biochemistry and Microbiology.
Show others and affiliations
2013 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, no 6, 2132-2146 p.Article in journal (Refereed) Published
Abstract [en]

Fibrosis is a deleterious consequence of chronic inflammation in a number of human pathological states ultimately leading to, if not perturbed to organ dysfunction and failure. Two key processes in fibrosis are activation of blood vessels and connective tissue cells leading to excess deposition of ECM components; collagen type I being the most abundant. In the present study the effects of two growth factors known to be important in the fibrotic process, namely PDGF-B and TGF-β1, were studied. Adenoviral vectors engineered to express PDGF-B or TGF-β1 were introduced into mouse skin thereby inducing a transient over-expression of either growth factor. After 3, 7 and 14 days post injection, tissues were harvested and morphology and protein expression were examined on plastic embedded 1 µm thick sections and by immunohistochemistry on frozen sections, respectively. Over-expression of both TGF-β1 and PDGF-B lead to a fibrotic response consisting of a marked macrophage influx as well as an expansion of the connective tissue cell population. In both conditions the latter originated from microvascular pericytes. The resulting phenotype of the emerging connective tissue cell population differed between PDGF-B and TGF-β1 treated skin.  In tissues over expressing PDGF-B but not TGF-β1 the fibrotic process was partially reversible. Both growth factors were able to initiate, but neither were able to sustain the process of angiogenesis, which lead to vascular regression. PDGF-B but not TGF-β1 was able to stimulate but not maintain a distinct form of angiogenesis i.e. glomeruloid body formation. In conclusion, over-expression of PDGF-B and TGF-β1 in normal skin resulted in the emergence of connective tissue cells differing in their phenotype, originating in both cases from a common cell namely the microvascular pericyte. Therefore the vasculature and the fibrotic process are linked in a previously unrecognized way.

Place, publisher, year, edition, pages
2013. Vol. 182, no 6, 2132-2146 p.
Keyword [en]
fibrosis, chronic inflammation, extracellular matrix, myofibroblast, pericyte, adenovirus, in vivo, PDGF-B, TGF-beta
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-120884DOI: 10.1016/j.ajpath.2013.01.054ISI: 000319781800019OAI: oai:DiVA.org:uu-120884DiVA: diva2:304107
Available from: 2010-03-17 Created: 2010-03-17 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. Extracellular Matrix and Connective Tissue Cells of the Tumor Microenvironment
Open this publication in new window or tab >>Extracellular Matrix and Connective Tissue Cells of the Tumor Microenvironment
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In addition to malignant cells, solid tumors comprise supporting stromal tissue that consists of extra cellular matrix (ECM), connective tissue cells, inflammatory cells and blood vessels. The stromal compartment and the malignant cells together shape the tumor microenvironment that in turn determines tumor progression and efficacy of anti-tumor treatments. In this thesis, studies that investigate the roles of different kinds of interactions between tumor cells and stromal cells were undertaken. Further, growth factors that have important roles in interactions between tumor cells and stromal cells were investigated in a non-tumor environment. Tumor cells were found to modulate the response to the platelet derived growth factor  (PDGF) by microvascular pericytes, a cell type found in the vasculature of solid tumors. The importance of this growth factor in biology of tumors has earlier been shown, but here it was shown that PDGF also modulate the ECM phenotype of solid tumors. The ECM of tumors treated with an inhibitor of PDGF receptor (PDGFR) signaling induced a less fibrotic collagen scaffold, which could explain how PDGFR inhibition in earlier reports lowered tumor interstitial fluid pressure (IFP). Lowering the normally high IFP in tumors increases efficacy of chemotherapy. The integrin αVβ3 is activated downstream of PDGF-B in acute inflammations, and this integrin is important for raising IFP in loose connective tissue in such conditions. However, in tumors we found that lack of the β3 subunit lead to an increased IFP, which were attributed to a more fibrotic ECM phenotype. In addition to PDGF-B, transforming growth factor β (TGFβ) is an important growth factor in the biology of tumors. These two growth factors were separately overexpressed in mouse skin and they both induced an inflammatory response. Expressed in a tumor free context, they evoked a response that was in many ways reminiscent of what can be observed in the tumor microenvironment. This thesis contributes further understanding of how the complex tumor microenvironment affects the phenotype of solid tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 613
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-132855 (URN)978-91-554-7927-5 (ISBN)
Public defence
2010-12-09, B21, BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2010-11-17 Created: 2010-10-27 Last updated: 2011-01-13Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Rodriguez, AlejandroFriman, TomasSundberg, Christian

Search in DiVA

By author/editor
Rodriguez, AlejandroFriman, TomasSundberg, Christian
By organisation
Department of Medical Biochemistry and MicrobiologyDepartment of Women's and Children's Health
In the same journal
American Journal of Pathology
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 759 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf