Impaired collagen fibril assembly in keloids with enhanced expression of lumican and collagen V

Zhou, Boya; Tu, Tian Ming; Gao, Zhen; Wu, Xiaoli; Wang, Wenbo; Liu, Wei

doi:10.1016/j.abb.2020.108676

Cited by 15 publications

(14 citation statements)

References 33 publications

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“…The characteristic length-scale of this phase should be slightly larger than the fibril diameter, if the fibrils are closely packed. Recent electron microscopy analysis of collagen fibrils by Zhou et al [ 7 ] have reported a mean diameter value of ~70 nm for keloid tissue versus ~120 nm for extra-lesional skin, which is, as expected, slightly smaller than the expected IFC spacings found here, and indicates an interfibrillar spacing of ~20–30 nm in regions with a significant amount of the IFC scattering component. The electron density difference between the interfibrillar matrix (PGs, elastin, NCPs, water) and the collagen fibrils contributes to the strong X-ray contrast leading to clear IFC peaks.…”

Section: Discussionsupporting

confidence: 74%

“…A macroscopic mechanical stress–strain curve of a keloid is shown in Appendix A Figure A2 , showing a linear behavior up to ~20% of nominal strain with a modulus (680 kPa) intermediate between the tendon and the skin (the reference lines for the tendon [ 53 , 54 ], dermis and hypodermis [ 55 ] layers of skin are shown on the figure). Recent atomic-force microscopy measurements report that a keloid has slightly lower values for modulus versus normal skin (~35 MPa vs. 45 MPa), but these are ~2 orders of magnitude larger than the macroscopic tissue modulus reported here [ 7 ]; small scale probes such as atomic force microscopy probes could report higher values of stiffness if weaker interfaces at larger scales are not considered.…”

Section: Discussioncontrasting

confidence: 55%

“…The electron density difference between the interfibrillar matrix (PGs, elastin, NCPs, water) and the collagen fibrils contributes to the strong X-ray contrast leading to clear IFC peaks. The wider IFC peak width relative to the meridional (IFC: 0.016 vs. collagen: 0.003 nm −1 ) may be due to heterogeneity in fibrillar radii (also seen in [ 7 ]).…”

Section: Discussionmentioning

confidence: 99%

“…However, limited experimental data exist on small-scale (collagen fibril level) mechanics in fibrosis. Lower maximum force has been reported [ 7 ], but deformation mechanisms of the collagenous fibrillar ECM have not been explored. Developing probes of the fibrillar ECM mechanics in fibrotic conditions would enable early onset detection and understanding mechanobiological pathways.…”

Section: Introductionmentioning

confidence: 99%

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Investigating the Fibrillar Ultrastructure and Mechanics in Keloid Scars Using In Situ Synchrotron X-ray Nanomechanical Imaging

et al. 2022

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Fibrotic scarring is prevalent in a range of collagenous tissue disorders. Understanding the role of matrix biophysics in contributing to fibrotic progression is important to develop therapies, as well as to elucidate biological mechanisms. Here, we demonstrate how microfocus small-angle X-ray scattering (SAXS), with in situ mechanics and correlative imaging, can provide quantitative and position-resolved information on the fibrotic matrix nanostructure and its mechanical properties. We use as an example the case of keloid scarring in skin. SAXS mapping reveals heterogeneous gradients in collagen fibrillar concentration, fibril pre-strain (variations in D-period) and a new interfibrillar component likely linked to proteoglycans, indicating evidence of a complex 3D structure at the nanoscale. Furthermore, we demonstrate a proof-of-principle for a diffraction-contrast correlative imaging technique, incorporating, for the first time, DIC and SAXS, and providing an initial estimate for measuring spatially resolved fibrillar-level strain and reorientation in such heterogeneous tissues. By application of the method, we quantify (at the microscale) fibrillar reorientations, increases in fibrillar D-period variance, and increases in mean D-period under macroscopic tissue strains of ~20%. Our results open the opportunity of using synchrotron X-ray nanomechanical imaging as a quantitative tool to probe structure–function relations in keloid and other fibrotic disorders in situ.

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Section: Discussionsupporting

confidence: 74%

Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigating the Fibrillar Ultrastructure and Mechanics in Keloid Scars Using In Situ Synchrotron X-ray Nanomechanical Imaging

et al. 2022

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“…In that regard, it is noteworthy that keloids seem to occur more often in patients exhibiting clinical endothelial dysfunction [ 54 ]. The finding that Lumican, a collagen fibril assembly regulator, and collagen V levels appear to be highly overexpressed in keloid tissues [ 55 ] support the hypothesis that increased collagen levels contribute to keloid and hypertrophic scarring.…”

Section: Reviewmentioning

confidence: 87%

Epigenetic Influences on Wound Healing and Hypertrophic-Keloid Scarring: A Review for Basic Scientists and Clinicians

Thomas¹,

Farah²,

Millis³

2022

Cureus

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Primary care physicians and dermatologists are challenged by patients affected by keloid or hypertrophic scarring resulting from accidental wounding, surgical incisions, tattooing, or “branding” procedures to demonstrate their association with a specific culture, fraternity, or cult. The dysregulated wound healing associated with keloids and hypertrophic scarring adversely affects genetically susceptible individuals, especially persons of color with Fitzpatrick Skin types IV-VI. Although the specific mechanisms of bulky hypertrophic/keloid scarring and its association with oxidative stress and inflammation remain unclear, the current knowledge base is sufficient to provide some guidance to health practitioners who must serve, treat, and counsel affected individuals. This review focuses on providing insight to healthcare professionals about the role of epigenetics, oxidative stress, poor local oxygenation, and its relationship to impaired wound healing. The goal is to promote further research on bulky hypertrophic and keloid scarring for its prevention and to develop evidence-based clinical guidelines for optimal treatment.

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Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

et al. 2022

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Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8-10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Results Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R 2 = 0.60, P < 0.01) and III (R 2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R 2 = 0.28, P = 0.05) and interstitial (R 2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (À15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer (À8.9%, P < 0.001) collagen fibres. Conclusions The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.

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Impaired collagen fibril assembly in keloids with enhanced expression of lumican and collagen V

Cited by 15 publications

References 33 publications

Investigating the Fibrillar Ultrastructure and Mechanics in Keloid Scars Using In Situ Synchrotron X-ray Nanomechanical Imaging

Investigating the Fibrillar Ultrastructure and Mechanics in Keloid Scars Using In Situ Synchrotron X-ray Nanomechanical Imaging

Epigenetic Influences on Wound Healing and Hypertrophic-Keloid Scarring: A Review for Basic Scientists and Clinicians

Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

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