The ECM as a driver of fibroblast senescence and disrupted epithelial repair in IPF

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a mean survival of 3-5 years after diagnosis. IPF is characterised by accumulation of fibroblasts and extracellular matrix (ECM) leading to stiffening, and destruction of lung parenchyma and alveoli. The exact mechanisms that underlie IPF pathology remain unclear, but evidence suggests that cellular senescence, a hallmark of ageing, may play an important role in disease development, with specific changes observed in the ECM also recognised as major contributors to disease progression. However, the exact role of fibroblast senescence and the regulation of senescence by the ECM remains to be elucidated. The aim of this thesis was to investigate the contribution of ECM to fibroblast senescence, and the subsequent impact on alveolar cell regeneration.
    In lung fibroblasts cultured on stiff matrices or on ECM deposited by IPF or non-IPF fibroblasts we analysed markers of senescence, and then assessed the effect of fibroblast senescence on alveolar cell regeneration.
    Matrices mimicking IPF lung tissue stiffness upregulated cellular senescence and fibrosis markers; α-smooth muscle actin, collagen 1α1, fibulin-1, Interleukin-6 and decorin. IPF fibroblast-deposited-ECM did not directly modulate these senescence markers, but rather induced upregulation of transforming growth factor-β1 and connective tissue growth factor. Finally, senescence and IPF fibroblasts reduced proliferation of alveolar epithelial cells, while the presence of fibroblasts, independent of disease status, induced epithelial cell migration.
    These studies indicate that IPF ECM is a strong regulator of cell function, while fibroblast senescence leads to impaired wound healing of alveolar epithelial cells.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Burgess, Janette, Supervisor
    • Knight, Darryl A., Supervisor, External person
    • Grainge, Christopher L, Co-supervisor, External person
    • Pouwels, Daan, Co-supervisor
    • Schuliga, Michael, Co-supervisor, External person
    Award date8-Sep-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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