Biology subjects

Screen, H. R. C.

Publications and source records attributed to Screen, H. R. C..

5 recordsLinked to original sources

bioRxiv2025

Human coronary artery tri-culture organ-chip recapitulates anti-inflammatory effect of pulsatile wall strain

Inflammation is a precursor to vascular diseases, including atherosclerosis, and is modulated by the local biomechanical environment. There is an urgent need for improved in vitro models, to advance understanding, and to test new therapeutic approaches.. This study describes the development and characterization of a human coronary artery organ-chip model of vascular inflammation, with physiological biomechanical stimulation. Human coronary artery endothelial cells and smooth muscle cells were cultured on appropriate extracellular matrices in the two adjoining channels of the Chip-S1(R) from Emulate Inc. Both endothelial and smooth muscle cells demonstrated characteristic phenotypic identity, shown by expression of CD31 and -SMA respectively. Application of physiological pulsatile tensile strain induced alignment of both cell types, perpendicular to strain direction, as seen in vivo. Addition of TNF- to the vascular channel drove an inflammatory response in both cell types, shown by upregulation of ICAM-1 and P65, and attachment and invasion of circulating THP-1 monocytes. Strain field analysis revealed pressure-dependent spatial variation with 12% strain in the center of the chip, and 5% towards the ends. Pulsatile tensile strain reduced the inflammatory response to TNF- with a greater localized inflammatory response in areas of lower strain, further replicating in vivo behavior. In conclusion, we present a fully characterized, tri-culture model of the human coronary artery which recapitulates the physiological effects of pulsatile vessel dilation on morphology and localized inflammatory susceptibility. Our model was developed upon a commercially-available, organ-chip platform, allowing for rapid adoption for therapeutic testing, and fundamental discovery science.

bioengineering↗

bioRxiv2023

The interfascicular matrix of energy storing tendons houses heterogenous cell populations disproportionately affected by ageing

Energy storing tendons such as the human Achilles and equine superficial digital flexor tendon (SDFT) are prone to injury, with incidence increasing with ageing. The interfascicular matrix (IFM), which binds tendon fascicles, plays a key role in energy storing tendon mechanics, and ageing alterations to the IFM negatively impact tendon function. While the mechanical role of the IFM in tendon function is well-established, the biological role of IFM-resident cell populations remains to be elucidated. Therefore, the aim of this study was to identify IFM-resident cell populations and establish how these populations are affected by ageing. Cells from young and old SDFTs were subjected to single cell RNA-sequencing, and immunolabelling for markers of each resulting population used to localise cell clusters. Eleven cell clusters were identified, including tenocytes, endothelial cells, mural cells and immune cells. One tenocyte cluster localised to the fascicular matrix, whereas nine clusters localised to the IFM. Interfascicular tenocytes and mural cells were preferentially affected by ageing, with differential expression of genes related to senescence, dysregulated proteostasis and inflammation. This is the first study to uncover the importance of the IFM niche for a diverse range of cell populations, and to identify age-related alterations specific to IFM-localised cells.

cell biology↗

bioRxiv2021

Structure-function Specialisation of the Interfascicular Matrix in the Human Achilles Tendon

ObjectiveTendon consists of highly aligned collagen-rich fascicles surrounded by interfascicular matrix (IFM). Some tendons act as energy stores to improve locomotion efficiency; these tendons are prone to debilitating injuries, the incidence of which increases with ageing. In equine tendons, energy storage is achieved primarily through specialisation of the IFM. However, no studies have investigated IFM structure-function specialisation in human tendons. Here, we compare the positional anterior tibialis and energy storing Achilles tendons, testing the hypothesis that the Achilles IFM has specialised composition and mechanical properties, which are lost with ageing. MethodsWe used a multidisciplinary combination of mechanical testing, immunolocalisation and proteomics to investigate structure-function specialisations in functionally distinct human tendons and how these are altered with ageing. ResultsThe IFM in the energy storing Achilles tendon is more elastic and fatigue resistant than the IFM in the positional anterior tibialis tendon, with a trend towards decreased fatigue resistance with age in the Achilles IFM. With ageing, alterations occur predominantly to the proteome of the Achilles IFM. ConclusionThe Achilles tendon IFM is specialised for energy storage, and changes to its proteome with ageing are likely responsible for the observed trends towards decreased fatigue resistance. Knowledge of key energy storing specialisations and their changes with ageing offers insight towards developing effective treatments for tendinopathy. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIEnergy storing tendons in animals and humans are particularly prone to tendinopathy and the incidence increases with increasing age. C_LIO_LIPrevious work in some animal models has shown that the specialisation of tendon properties for energy storage is achieved primarily through adaptation of the interfascicular matrix, with specialisation lost in ageing. However, the structural specialisations that provide the human Achilles tendon with its energy storing ability, and how these are affected by ageing, remain to be established. C_LI What does this study add?O_LIWe demonstrate that the interfascicular matrix in the human Achilles tendon is specialised for energy storing, with increased elastic recoil and fatigue resistance, and that these specialisations are partially lost with ageing, likely due to alterations to the proteome of the interfascicular matrix. C_LI How might this impact on clinical practice or future developments?O_LIShort term, the specialist IFM mechanics we have demonstrated can be detected with new developments in ultrasound functional imaging, offering improved opportunities for contextual tendinopathy diagnostics. Personalised rehabilitation programmes can now be explored and designed specifically to target IFM mechanics. C_LIO_LILonger term, the knowledge of key specialisations in injury prone energy storing tendons and how they are affected by ageing, offers crucial insight towards developing cell or tissue engineering treatments targeted at restoring tendon structure and function post-injury, specifically targeted at the IFM. C_LI

bioengineering↗

bioRxiv2020

Elastase treatment of tendon specifically impacts the mechanical properties of the interfascicular matrix

The tendon interfascicular matrix (IFM) binds tendon fascicles together. As a result of its low stiffness behaviour under small loads, it enables non-uniform loading and increased overall extensibility of tendon by facilitating fascicle sliding. This function is particularly important in energy storing tendons, with previous studies demonstrating enhanced extensibility, recovery and fatigue resistance in the IFM of energy storing compared to positional tendons. However, the compositional specialisations within the IFM that confer this behaviour remain to be elucidated. It is well established that the IFM is rich in elastin, therefore we sought to test the hypothesis that elastin depletion (following elastase treatment) will significantly impact IFM, but not fascicle, mechanical properties, reducing IFM resilience in all samples, but to a greater extent in younger tendons, which have a higher elastin content. Using a combination of quasi-static and fatigue testing, and optical imaging, we confirmed our hypothesis, demonstrating that elastin depletion resulted in significant decreases in IFM viscoelasticity, fatigue resistance and recoverability compared to untreated samples, with no significant changes to fascicle mechanics. Ageing had little effect on fascicle or IFM response to elastase treatment. This study offers a first insight into the functional importance of elastin in regional specific tendon mechanics. It highlights the important contribution of elastin to IFM mechanical properties, demonstrating that maintenance of a functional elastin network within the IFM is essential to maintain IFM and thus tendon integrity.

bioengineering↗

bioRxiv2020

Postnatal mechanical loading drives adaptation of tissues primarily through modulation of the non-collagenous matrix

Mature connective tissues demonstrate highly specialised properties, remarkably adapted to meet their functional requirements. Tissue adaptation to environmental cues can occur throughout life and poor adaptation commonly results in injury. However, the temporal nature and drivers of functional adaptation remain undefined. Here, we explore functional adaptation and specialisation of mechanically loaded tissues using tendon; a simple aligned biological composite, in which the collagen (fibre phase) and surrounding predominantly non-collagenous matrix (matrix phase) can be interrogated independently. Using an equine model of late development, we report the first phase-specific analysis of biomechanical, structural and compositional changes seen in functional adaptation, demonstrating adaptation occurs postnatally, following mechanical loading, and is almost exclusively localised to the non-collagenous matrix phase. These novel data redefine adaptation in connective tissue, highlighting the fundamental importance of non-collagenous matrix and suggesting that regenerative medicine strategies should change focus from the fibrous to the non-collagenous matrix phase of tissue.

cell biology↗