Stefania Wunderli


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Wunderli

First Name

Stefania

ORCID

0000-0001-7152-0781

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2014 - 201922020 - 20212
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Publications 1 - 4 of 4
  • Sustained mechanical tension governs fibrogenic activation of tendon stromal cells in systemic sclerosis
    Item type: Working Paper
    Hussien, Amro A.; Knell, Robert; Renoux, Florian; et al. (2021)
    bioRxiv
    Fibrosis is a pathological outcome of aberrant repair responses in systemic sclerosis and affects many tissues, including tendons. Progressive matrix stiffening is a key feature of this pathological remodeling. How dysregulated tissue mechanics contribute to the persistence of the fibrotic phenotype has been obscured by limited availability of experimental tissue models that are both controllable and capture essential aspects of the tendon biophysical niche. Here, we developed a modular, cantilever-based platform that allows culture of 3D tendon-like constructs under easily variable static tension, emulating this central tendon-specific structure function relationship. The system reveals that elevated matrix tension instigates fibroblast-to-myofibroblast activation eliciting scar-like phenotypes in vitro. By using this mechano-culture system and preclinical and clinical models of systemic sclerosis, we further show that 3D matrix stiffness is inversely correlated with the transcription of major pro-fibrotic collagens, but positively correlate with the expression of markers of stromal-immune interactions. Co-culture of tendon stromal fibroblasts and bone marrow-derived macrophages override stiffness-mediated downregulation of matrix transcription, suggesting that normal tension mediated checkpoints are superseded by the local tissue immune state. Our study highlights the power of 3D reductionist approaches in dissecting the contribution of the elevated matrix tension to the positive feedforward loops between activated fibroblasts and progressive ECM stiffening in systemic sclerosis.
  • Tendon response to matrix unloading is determined by the patho-physiological niche
    Item type: Working Paper
    Wunderli, Stefania; Blache, Ulrich; Beretta Piccoli, Agnese; et al. (2019)
    bioRxiv
    Aberrant matrix turnover with elevated matrix proteolysis is a hallmark of tendon pathology. While tendon disease mechanisms remain obscure, mechanical cues are central regulators. Unloading of tendon explants in standard culture conditions provokes rapid cell-mediated tissue breakdown. Here we show that biological response to tissue unloading depends on the mimicked physiological context. Our experiments reveal that explanted tendon tissues remain functionally stable in a simulated avascular niche of low temperature and oxygen, regardless of the presence of serum. This hyperthermic and hyperoxic niche-dependent catabolic switch was shown by whole transcriptome analysis (RNA-seq) to be a strong pathological driver of an immune-modulatory phenotype, with a stress response to reactive oxygen species (ROS) and associated activation of catabolic extracellular matrix proteolysis that involved lysosomal activation and transcription of a range of proteolytic enzymes. Secretomic and degradomic analysis through terminal amine isotopic labeling of substrates (TAILS) confirmed that proteolytic activity in unloaded tissues was strongly niche dependent. Through targeted pharmacological inhibition we isolated ROS mediated oxidative stress as a major checkpoint for matrix proteolysis. We conclude from these data that the tendon stromal compartment responds to traumatic mechanical unloading in a manner that is highly dependent on the extrinsic niche, with oxidative stress response gating the proteolytic breakdown of the functional collagen backbone.
  • Tendon response to matrix unloading is determined by the patho-physiological niche
    Item type: Journal Article
    Wunderli, Stefania; Blache, Ulrich; Beretta Piccoli, Agnese; et al. (2020)
    Matrix Biology
    Although the molecular mechanisms behind tendon disease remain obscure, aberrant stromal matrix turnover and tissue hypervascularity are known hallmarks of advanced tendinopathy. We harness a tendon explant model to unwind complex cross-talk between the stromal and vascular tissue compartments. We identify the hypervascular tendon niche as a state-switch that gates degenerative matrix remodeling within the tissue stroma. Here pathological conditions resembling hypervascular tendon disease provoke rapid cell-mediated tissue breakdown upon mechanical unloading, in contrast to unloaded tendons that remain functionally stable in physiological low-oxygen/-temperature niches. Analyses of the stromal tissue transcriptome and secretome reveal that a stromal niche with elevated tissue oxygenation and temperature drives a ROS mediated cellular stress response that leads to adoption of an immune-modulatory phenotype within the degrading stromal tissue. Degradomic analysis further reveals a surprisingly rich set of active matrix proteases behind the progressive loss of tissue mechanics. We conclude that the tendon stromal compartment responds to aberrant mechanical unloading in a manner that is highly dependent on the vascular niche, with ROS gating a complex proteolytic breakdown of the functional collagen backbone.
  • Dose- and time-dependent effects of genipin crosslinking on cell viability and tissue mechanics - Toward clinical application for tendon repair
    Item type: Journal Article
    Fessel, Gion; Cadby, Jennifer; Wunderli, Stefania; et al. (2014)
    Acta Biomaterialia
    The crosslinking agent genipin is increasingly invoked for the mechanical augmentation of collagen tissues and implants, and has previously been demonstrated to arrest mechanical damage accumulation in various tissues. This study established an in vitro dose–response baseline for the effects of genipin treatment on tendon cells and their matrix, with a view to in vivo application to the repair of partial tendon tears. Regression models based on a broad range of experimental data were used to delineate the range of concentrations that are likely to achieve functionally effective crosslinking, and predict the corresponding degree of cell loss and diminished metabolic activity that can be expected. On these data, it was concluded that rapid mechanical augmentation of tissue properties can only be achieved by accepting some degree of cytotoxicity, yet that post-treatment cell survival may be adequate to eventually repopulate and stabilize the tissue. On this basis, development of delivery strategies and subsequent in vivo study seems warranted.
Publications 1 - 4 of 4