Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis

Júnior, Constança; Narciso, Maria; Marhuenda, Esther; Almendros, Isaac; Farré, Ramón; Navajas, Daniel; Otero, Jorge; Gavara, Núria

doi:10.3390/ijms222312928

Cited by 19 publications

(24 citation statements)

References 51 publications

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“…Therefore, biomechanical characterizations of the decellularized tissue were obtained, which indicated similar stiffness for dLu and dLN, with a notable variability in macro-scale stiffness for dLN. Although the obtained mechanical properties (Young’s Modulus) of dLu are comparable to literature, these properties are only known for animal-derived decellularized ECM, non-decellularized human ECM or engineered hydrogels ( 58 – 62 ), extending the relevance of this study. Mechanical characterization of human lymph node ECM is absent in literature.…”

Section: Discussionsupporting

confidence: 60%

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

et al. 2023

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Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis.

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Section: Discussionsupporting

confidence: 60%

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

et al. 2023

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“…Our results show an increase in elastin in the bleomycin-treated lungs with time, peaking at day 28, whilst in the PBS-treated lungs its content peaks at day 14 and is followed by a decrease. Thus, we can hypothesise that the presence of elastin might contribute to the turnover of the disease, as previous results reported by our lab suggested that there is a transition of behaviour from strain-hardening to strain-softening of the ECM that might work as a protection mechanism of the lung to prevent fibroblasts of proliferating after their initial activation [ 42 ]. The increase in elastin in the PBS-treated samples could be partly responsible for this turnover due to its physical role on the mechanical response of the lung ECM.…”

Section: Discussionmentioning

confidence: 75%

Multi-Step Extracellular Matrix Remodelling and Stiffening in the Development of Idiopathic Pulmonary Fibrosis

Júnior

Ulldemolins

Narciso

et al. 2023

IJMS

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The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided by the ECM. Lung fibrosis displays an aberrant increased deposition of ECM which likely changes filament organization and stiffens the ECM, thus upregulating the profibrotic profile of pulmonary cells. We have previously used AFM to assess changes in the Young’s Modulus (E) of the ECM in the lung. Here, we perform further ECM topographical, mechanical and viscoelastic analysis at the micro- and nano-scale throughout fibrosis development. Furthermore, we provide nanoscale correlations between topographical and elastic properties of the ECM fibres. Firstly, we identify a softening of the ECM after rats are instilled with media associated with recovery of mechanical homeostasis, which is hindered in bleomycin-instilled lungs. Moreover, we find opposite correlations between fibre stiffness and roughness in PBS- vs bleomycin-treated lung. Our findings suggest that changes in ECM nanoscale organization take place at different stages of fibrosis, with the potential to help identify pharmacological targets to hinder its progression.

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“…CD11b has been reported as a key biomarker in immune cells for the progression of diseases like cancer and autoimmunity 25,[28][29][30][91][92][93] . Given the growing evidence that cell elasticity and fluidity suffer alterations in disease, adhesion and mechanics of immune cells may appear as relevant biomarkers 26,[94][95][96][97][98][99][100][101][102][103] .…”

Section: Discussionmentioning

confidence: 99%

Coupled mechanical mapping and interference contrast microscopy reveal viscoelastic and adhesion hallmarks of monocytes differentiation into macrophages

Eroles

López-Alonso

Ortega

et al. 2022

Preprint

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Monocytes in the blood torrent, when activated by pro-inflammatory signals, adhere to the vascular endothelium and migrate into the tissue for ultimately differentiate into macrophages. Mechanics and adhesion play a crucial role in macrophage functions, such as migration and phagocytosis. However, how monocytes change their adhesion and mechanical properties upon differentiation into macrophages is still not well understood.In this work, we combined atomic force microscopy (AFM) viscoelastic mapping with interference contrast microscopy (ICM) to simultaneously probe, at the single-cell level, viscoelasticity and adhesion during monocyte differentiation. THP-1 monocytic cells were differentiated into macrophages through phorbol 12-myristate 13-acetate (PMA). Morphological quantification was achieved using holographic tomography imaging and the expression of integrin subunit CD11b was tracked as a marker of differentiation.Holographic tomography proved to be a quantitative in vivo technique, revealing a dramatic increase in macrophage volume and surface area and two subpopulations, spread and round macrophages. AFM viscoelastic mapping revealed an increased stiffness and more solid-like behavior of differentiated macrophages, especially in the lamellipodia and microvilli regions. Differentiated cells revealed an important increase of the apparent Young’s modulus (E0) and a decrease of cell fluidity (β) on differentiated cells, which correlated with an increase in adhesion area. Macrophages with a spreading phenotype enhanced these changes. Remarkably, when adhesion was eliminated, differentiated macrophages remained stiffer and more solid-like than monocytes, suggesting a permanent reorganization of the cytoskeleton. We speculate that the more solid-like microvilli and lamellipodia might help macrophages to minimize energy dissipation during mechanosensitive activity, such as phagocytosis, making it more efficient. Our proposed approach revealed viscoelastic and adhesion hallmarks of monocyte differentiation that may be important for biological function.

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Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis

Cited by 19 publications

References 51 publications

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

Multi-Step Extracellular Matrix Remodelling and Stiffening in the Development of Idiopathic Pulmonary Fibrosis

Coupled mechanical mapping and interference contrast microscopy reveal viscoelastic and adhesion hallmarks of monocytes differentiation into macrophages

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