Michael Sherratt

Michael Sherratt
The University of Manchester · Institute of Inflammation and Repair

About

202
Publications
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Publications

Publications (202)
Article
Full-text available
Extracellular matrix (ECM) in the intervertebral disc (IVD), lung and artery are thought to undergo the age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exp...
Article
Full-text available
Extracellular matrix (ECM) proteins confer biomechanical properties, maintain cell phenotype and mediate tissue repair (via release of sequestered cytokines and proteases). In contrast to intracellular proteomes, where proteins are monitored and replaced over short time periods, many ECM proteins function for years (decades in humans) without repla...
Article
Full-text available
Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle to detect low-abundance proteins. To ov...
Article
Full-text available
Diabetes is a major concern of our society as it affects one person out of 11 around the world. Elastic fiber alterations due to diabetes increase the stiffness of large arteries, but the structural effects of these alterations are poorly known. To address this issue, we used synchrotron X-ray microcomputed tomography with in-line phase contrast to...
Preprint
Full-text available
Extracellular matrix (ECM) in the intervertebral disc (IVD), lung and artery are thought to undergo the age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exp...
Article
Full-text available
Exposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interac...
Article
Many soft tissues, such as the intervertebral disc (IVD), have a hierarchical fibrous composite structure which suffers from regional damage. We hypothesise that these tissue regions have distinct, inherent fibre structure and structural response upon loading. Here we used synchrotron computed tomography (sCT) to resolve collagen fibre bundles (∼5μ...
Article
Full-text available
The arterial wall consists of three concentric layers: intima, media, and adventitia. Beyond their resident cells, these layers are characterized by an extracellular matrix (ECM), which provides both biochemical and mechanical support. Elastin, the major component of arterial ECM, is present in the medial layer and organized in concentric elastic l...
Article
Full-text available
In ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural diff...
Article
Full-text available
Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bo...
Preprint
In ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural diff...
Article
Chronic UVR exposure of human skin can result in photo-ageing which manifests both externally and internally (as remodelling of skin layers including the extracellular matrix-rich dermis). However, the intermittent nature of UVR exposure over a timescale of decades combined with the longevity of many structural dermal proteins makes the identificat...
Article
Full-text available
Ozols and Eckersley are equally contributing joint first authors. Although dysfunctional protein homeostasis (proteostasis) is a key factor in many age‐related diseases, the untargeted identification of structurally modified proteins remains challenging. Peptide location fingerprinting is a proteomic analysis technique capable of identifying struct...
Article
Full-text available
Both protease- and reactive oxygen species (ROS)-mediated proteolysis are thought to be key effectors of tissue remodeling. We have previously shown that comparison of amino acid composition can predict the differential susceptibilities of proteins to photo-oxidation. However, predicting protein susceptibility to endogenous proteases remains challe...
Preprint
Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bo...
Preprint
Full-text available
Age, disease, and exposure to environmental factors can induce tissue remodelling and alterations in protein structure and abundance. In the case of human skin, ultraviolet radiation (UVR)-induced photo-ageing has a profound effect on dermal extracellular matrix (ECM) proteins. We have previously shown that ECM proteins rich in UV-chromophore amino...
Chapter
Full-text available
Age-related changes in elastin refer to modifications such as nonenzymatic cross-linking and/ or proteolytic degradation, which adversely affect the mechanical and biochemical properties of elastin-rich tissues and organs. Elastin (in combination with other extracellular matrix components) forms elastic fibers. These structures are primarily respon...
Preprint
Full-text available
Although dysfunctional protein homeostasis (proteostasis) is a key factor in many age-related diseases, the untargeted identification of structural modifications in proteins remains challenging. Peptide location fingerprinting is a proteomic analysis technique capable of identifying structural modification-associated differences in mass spectrometr...
Article
Cranial cruciate ligament disease (CCLD) is the most common cause of pelvic limb lameness in dogs but its precise aetiopathogenesis is uncertain. Fibrillin microfibrils (FM) are complex macro-molecular assemblies found in many tissues including ligaments, where they are thought to play an important mechanical role. We hypothesised that FM ultrastru...
Article
Fibrillin-rich microfibrils (FRMs) constitute integral components of the dermal elastic fibre network with a distinctive ultrastructural 'beads-on-a-string' appearance that can be visualised using atomic force microscopy and characterised by measurement...
Article
Full-text available
Vascular calcification describes the formation of mineralized tissue within the blood vessel wall, and it is highly associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. In this article, we briefly review different rodent models used to study vascular calcification i...
Article
The dermal elastic fibre network is the primary effector of skin elasticity, enabling it to extend and recoil many times over the lifetime of the individual. Fibrillin‐rich microfibrils (FRMs) constitute integral components of the elastic fibre network, with their distribution showing differential deposition in the papillary dermis across individua...
Preprint
Arterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKCα expression increases high phosphate-induced mineral deposition by vascular smooth muscle cells in vitro. This new study tests the hypothesis that PKCα regulates uremia-induced medial calcification in vi...
Article
Full-text available
One of the major functions of human skin is to provide protection from the environment. Whilst we cannot entirely avoid, for example, sun‐exposure, it is likely that exposure to other environmental factors could impact cutaneous function. A number of studies have identified smoking as one such factor that leads to both facial wrinkle formation and...
Article
Full-text available
In contrast to the dynamic intracellular environment, structural extracellular matrix (ECM) proteins with half-lives measured in decades, are susceptible to accumulating damage. Whilst conventional approaches suchas histology, immunohistochemistry and mass spectrometry are able to identify age- and disease-relatedchanges in protein abundance or dis...
Preprint
Full-text available
Remodelling of the dermal extracellular matrix makes a major contribution to skin fragility in the elderly. The peri-menopausal period in females is also associated with an age-like phenotype which can be reversed by hormone replacement therapy. This suggests a direct link between circulating hormone levels and tissue ageing. Despite work investiga...
Article
Circadian rhythms are daily oscillations that, in mammals, are driven by both a master clock, located in the brain, and peripheral clocks in cells and tissues. Approximately 10% of the transcriptome, including extracellular matrix components, is estimated to be under circadian control. Whilst it has been established that certain collagens and extra...
Chapter
In this chapter we discuss the molecular composition and structure of the epidermis, dermal-epidermal junction, dermis and hypodermis. We highlight the contribution of long-lived dermal collagens, elastic fibres, proteoglycans and hyaluronic acid to skin function and also consider the role of apparently “minor” skin components. In order to characte...
Article
The intervertebral disc (IVD) has a complex and multiscale extracellular matrix structure which provides unique mechanical properties to withstand physiological loading. Low back pain has been linked to degeneration of the disc but reparative treatments are not currently available. Characterising the disc’s 3D microstructure and its response in a p...
Conference Paper
Full-text available
Intimal calcification is the formation of mineralised tissue within atherosclerotic lesions and can lead to an increased risk of plaque rupture and mortality in man. Even though experimental data are sparse, it had been suggested that inhibiting protein kinase Cα (PKCα) may be of therapeutic benefit in atherosclerosis. However, we recently discover...
Conference Paper
Full-text available
Medial calcification is the formation of mineralised tissue within the smooth muscle layer of the vessel wall, and frequently occurs in patients with chronic kidney disease. Calcification within the medial layer of the vessel wall can reduce aortic and arterial elasticity, which impairs cardiovascular haemodynamics and results in a significantly el...
Preprint
Full-text available
Hormone deficiency has been widely linked to accelerated tissue ageing, and increased incidence of chronic degenerative disease. Furthermore, age-associated hormonal dysregulation is thought to be a major contributing factor to the increased fragility of aged skin. The ageing process is driven by an aggregation of damage to cells and extracellular...
Article
Lysyl oxidases (LOXs) play a central role in extracellular matrix remodeling during development and tumor growth and fibrosis through cross-linking of collagens and elastin. We have limited knowledge of the structure and substrate specificity of these secreted enzymes. LOXs share a conserved C-terminal catalytic domain but differ in their N-termina...
Article
Objective With increasing age skin is subject to alterations in its organisation, which impacts on its function as well as having clinical consequences. Proteomics is a useful tool for non‐targeted, semi‐quantitative simultaneous investigation of high numbers of proteins. In the current study we utilise proteomics to characterise and contrast age‐a...
Article
Full-text available
Photodamage in chronically sun-exposed skin manifests clinically as deep wrinkles and histologically as extensive remodelling of the dermal extracellular matrix (ECM) and in particular, the elastic fibre system. We have shown previously that loss of fibrillin microfibrils, a key elastic fibre component, is a hallmark of early photodamage and that t...
Article
Full-text available
Aortic wall remodelling is a key feature of both ageing and genetic connective tissue diseases, which are associated with vasculopathies such as Marfan syndrome (MFS). Although the aorta is a 3D structure, little attention has been paid to volumetric assessment, primarily due to the limitations of conventional imaging techniques. Phase-contrast mic...
Article
The measurement of the mechanical properties of skin (such as stiffness, extensibility and strength) is a key step in characterisation of both dermal ageing and disease mechanisms and in the assessment of tissue engineered skin replacements. However, the biomechanical terminology and plethora of mathematical analysis approaches can be daunting to t...
Data
Serial block-face SEM data set of the ciliary zonule. A movie showing a representative sub-set of the SBF-SEM image stack analyzed in Fig. 1D.
Data
3D rendering of ciliary zonule fibers. The movie shows 2D slices through the SBF-SEM data set shown in Fig. 1D before it is rendered in 3D. Individual ciliary zonules can be seen with circumferentially wrapped fibers around the perimeter. The contrast of the data has been inverted.
Data
3D segmentation of an individual ciliary zonule fiber. A movie of a 3D rendered segmented ciliary zonule fiber. The ciliary zonule fiber is shown in blue, and the more electron-dense fiber around the perimeter is shown in orange. A 2D orthogonal slice of the SBF-SEM data is also shown.
Article
Full-text available
Numerous pathologies lead to remodelling of the mammalian ventricle, often associated with fibrosis. Recent work in fish has shown that fibrotic remodelling of the ventricle is 'reversible', changing seasonally as temperature-induced changes in blood viscosity alter haemodynamic load on the heart. The atrial response to varying haemodynamic load is...
Article
Fibrillin microfibrils are evolutionarily ancient, structurally-complex extracellular polymers found in mammalian elastic tissues where they endow elastic properties, sequester growth factors and mediate cell signalling; thus, knowledge of their structure and organisation is essential for a more complete understanding of cell function and tissue mo...
Article
Full-text available
Fibrillin microfibrils are extensible polymers that endow connective tissues with long-range elasticity and have widespread distributions in both elastic and non-elastic tissues. They act as a template for elastin deposition during elastic fibre formation and are essential for maintaining the integrity of tissues such as blood vessels, lung, skin a...
Conference Paper
Human skin forms the main barrier between the internal system and the external environment. This barrier is crucial in two ways. First, it protects the internal system from external insults such as ultraviolet radiation and toxins. Second, it prevents excessive water loss and maintains water and electrolytes homeostasis. Tight junctions of the epid...
Article
Many biological tissues have a complex hierarchical structure allowing them to function under demanding physiological loading conditions. Structural changes caused by ageing or disease can lead to loss of mechanical function. Therefore, it is necessary to characterise tissue structure to understand normal tissue function and the progression of dise...
Data
Table S1 - Combined table of all fibrillin microfibril co-purifying proteins (Protein Prophet FDR<0.1%) identified using LC-MS/MS. Peptide spectrum matches (Peptide Prophet FDR<5%) are shown for each sample and for each tissue.
Data
Figure S1. The elastase method and advances in MS technology led to the improved detection of COL6A3 peptides compared to previous published efforts. The ability of the elastase method to produce COL6A3 peptides from a single human CB sample (F67) and single human skin sample (F49) is compared to efforts made by Beecher et al. 2011 (55) from a sing...
Article
Full-text available
Elastic fibres comprising fibrillin microfibrils and elastin are present in many tissues, including the skin, lung, and arteries where they confer elasticity and resilience. Although fibrillin microfibrils play distinct and tissue-specific functional roles, it is unclear whether their ultrastructure and composition differ between elastin-rich (skin...
Article
Full-text available
Defining protein composition is a key step in understanding the function of both healthy and diseased biological systems. There is currently little consensus between existing published proteomes in tissues such as the aorta, cartilage and organs such as skin. Lack of agreement as to both the number and identity of proteins may be due to issues in p...
Article
Full-text available
Although the composition and structure of cartilaginous tissues is complex, collagen II fibrils and aggrecan are the most abundant assemblies in the articular cartilage (AC) and nucleus pulposus (NP) of the intervertebral disc (IVD). Whilst structural heterogeneity of intact (three globular domain) aggrecan is well characterised, the extent of aggr...
Article
Full-text available
Intervertebral disc degeneration (IVDD) is linked to low back pain. Microstructural changes during degeneration have previously been imaged using 2D sectioning techniques and 3D methods which are limited to small specimens and prone to inducing artefacts from sample preparation. This study explores micro computed X-ray tomography (microCT) methods...
Article
Full-text available
Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis. Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its inter...
Article
A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However,...
Article
Full-text available
The efficacy of topical sunscreens is currently assessed by crude, costly and time consuming in vivo assays. We have previously demonstrated that components of the dermal extracellular matrix (ECM), rich in UV-absorbing amino acids, are susceptible to damage by solar simulated radiation (SSR) in vitro. Here we developed an in vitro method to test t...
Conference Paper
Many dermal extracellular matrix proteins function as part of multicomponent, supramolecular assemblies. For example, fibrillin-1 forms microfibrils (MFs) with a characteristic beads-on-a-string appearance. In skin, these associate with elastin to form elastic fibres and also act as stand-alone, candelabra-like structures in the papillary dermis. I...