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Defining the pericyte to fibroblast lineage
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

In the present study placental tissues were characterized in vivo with regards to markers expressed on pericytes, fibroblasts and collagen type I synthesis. Microvascular fragments (MVFs) isolated from human placentas had a phenotypical marker profile consistent with microvessels in situ. Cells emerging from MVFs from placenta express a marker profile consistent with a pericyte phenotype. Temporal studies identified three optimal time points (T0, T1 and T2) subsequent to the onset of cells emerging from MVFs for further analysis with regards to divergence in marker expression profiles. T0, T1 and T2 time points contained a population of cells with a cellular phenotype consistent with mesenchymal stem/progenitor cells, activated microvascular pericytes and mature connective tissue cells. Three discernable subpopulations of cells were identified i.e. Stro-1+/CD146+/podoplanin-, Stro-1-/CD146+/podoplanin- and Stro-1-/CD146-/podoplanin+ cells. Flow cytometry analysis allowed for the Stro-1-/CD146+/podoplanin- and Stro-1-/CD146-/podplanin+ cell populations to be further divided into 2 subgroups based on the expression of desmin, αSMA and TE-7. Five steps in the differentiation process from mesenchymal stem/progenitor cell to collagen type I producing fibroblast and the order by which they progressed could be defined by re-diversification studies i.e. ability of one population of cells to give rise to the other population of cells. Two in vivo experimental systems, TPA induced inflammation and excisional cutaneous wound healing were analyzed for the existence of slow cycling cells. The in vivo evidence shows that microvascular pericytes constitute a reservoir of stem/progenitor cells for pro-fibrotic connective tissue cells. This study presents novel evidence for a connective tissue cell lineage originating from a undifferentiated mesenchymal vessel associated cell population that via pericytes differentiate into pro-fibrotic fibroblasts.

Keyword [en]
pericyte fibroblast differentiation cell lineage mesenchymal stem cell
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; Microbiology; Cell Research
Identifiers
URN: urn:nbn:se:uu:diva-132610OAI: oai:DiVA.org:uu-132610DiVA: diva2:359884
Available from: 2010-11-01 Created: 2010-10-22 Last updated: 2011-06-28
In thesis
1. 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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Sundberg, Christian

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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Microbiology in the medical areaCell and Molecular Biology

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