Fiber alignment drives changes in architectural and mechanical features in collagen matrices

Taufalele, Paul V.; VanderBurgh, Jacob A.; Muñoz, Adam; Zanotelli, Matthew R.; Reinhart‐King, Cynthia A.

doi:10.1371/journal.pone.0216537

Cited by 105 publications

(83 citation statements)

References 39 publications

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“…2015; Taufalele et al . 2019). Here, we adapted polarized light microscopy with picrosirius red labelling of collagen used in tendon to analyse the alignment of collagen in skeletal muscle for the first time.…”

Section: Discussionmentioning

confidence: 99%

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Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

Brashear

Wohlgemuth

Gonzalez

et al. 2020

The Journal of Physiology

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Key points The amount of fibrotic material in dystrophic mouse muscles relates to contractile function, but not passive function. Collagen fibres in skeletal muscle are associated with increased passive muscle stiffness in fibrotic muscles. The alignment of collagen is independently associated with passive stiffness in dystrophic skeletal muscles. These outcomes demonstrate that collagen architecture rather than collagen content should be a target of anti‐fibrotic therapies to treat muscle stiffness. Abstract Fibrosis is prominent in many skeletal muscle pathologies including dystrophies, neurological disorders, cachexia, chronic kidney disease, sarcopenia and metabolic disorders. Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used mdx mice, a model for Duchenne muscular dystrophy that becomes fibrotic, and wildtype mice. In this model, extensor digitorum longus (EDL) muscle was significantly stiffer, but with similar total collagen, while the soleus muscle did not change stiffness, but increased collagen. The stiffness of the EDL was associated with increased collagen crosslinking as determined by collagen solubility. Measurement of ECM alignment using polarized light microscopy showed a robust relationship between stiffness and alignment for wildtype muscle that broke down in mdx muscles. Direct visualization of large collagen fibres with second harmonic generation imaging revealed their relative abundance in stiff muscles. Collagen fibre alignment was linked to stiffness across all muscles investigated and the most significant factor in a multiple linear regression‐based model of muscle stiffness from ECM parameters. This work establishes novel characteristics of skeletal muscle ECM architecture and provides evidence for a mechanical function of collagen fibres in muscle. This finding suggests that anti‐fibrotic strategies to enhance muscle function and excessive stiffness should target large collagen fibres and their alignment rather than total collagen.

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Section: Discussionmentioning

confidence: 99%

“…2015; Taufalele et al . 2019). In tendons it is well appreciated that decreased alignment of collagen yields a decreased stiffness (Lake et al .…”

Section: Introductionmentioning

confidence: 99%

Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

Brashear

Wohlgemuth

Gonzalez

et al. 2020

The Journal of Physiology

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“…Matrix crosslinks enhance stiffness independent of density yet similarly improve vessel outgrowth and branching (Bordeleau et al, 2017). Fibril alignment similarly affects the microscale matrix stiffness and porosity (Taufalele et al, 2019). Thus, neovessel navigation through tissues likely involves the complex interplay of matrix architecture, mechanical environment, and the spatiotemporal distribution of angiogenic factors.…”

Section: Introductionmentioning

confidence: 99%

Stromal Cells Promote Neovascular Invasion Across Tissue Interfaces

Strobel¹,

LaBelle

Krishnan

et al. 2020

Front. Physiol.

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Vascular connectivity between adjacent vessel beds within and between tissue compartments is essential to any successful neovascularization process. To establish new connections, growing neovessels must locate other vascular elements during angiogenesis, often crossing matrix and other tissue-associated boundaries and interfaces. How growing neovessels traverse any tissue interface, whether part of the native tissue structure or secondary to a regenerative procedure (e.g., an implant), is not known. In this study, we developed an experimental model of angiogenesis wherein growing neovessels must interact with a 3D interstitial collagen matrix interface that separates two distinct tissue compartments. Using this model, we determined that matrix interfaces act as a barrier to neovessel growth, deflecting growing neovessels parallel to the interface. Computational modeling of the neovessel/matrix biomechanical interactions at the interface demonstrated that differences in collagen fibril density near and at the interface are the likely mechanism of deflection, while fibril alignment guides deflected neovessels along the interface. Interestingly, stromal cells facilitated neovessel interface crossing during angiogenesis via a vascular endothelial growth factor (VEGF)-A dependent process. However, ubiquitous addition of VEGF-A in the absence of stromal cells did not promote interface invasion. Therefore, our findings demonstrate that vascularization of a tissue via angiogenesis involves stromal cells providing positional cues to the growing neovasculature and provides insight into how a microvasculature is organized within a tissue.

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“…2-b3). Thus, besides evaluation of mechanical properties of collagen fiber by AFM in different cancers (Plodinec et al, 2012; Nematbakhsh et al, 2017; Brauchle et al, 2018; Stylianou et al, 2018; Taufalele et al, 2019), the analytical study of micro-nano-textural attributes become important in diagnostics of OPMD.…”

Section: Discussionmentioning

confidence: 99%

Elucidation of Differential Nano-Textural Attributes for Normal Oral Mucosa and Pre-Cancer

et al. 2019

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Computational analysis on altered micro-nano-textural attributes of the oral mucosa may provide precise diagnostic information about oral potentially malignant disorders (OPMDs) instead of an existing handful of qualitative reports. This study evaluated micro-nano-textural features of oral epithelium from scanning electron microscopic (SEM) images and the sub-epithelial connective tissue from light microscopic (LM) and atomic force microscopic (AFM) images for normal and OPMD (namely oral sub-mucous fibrosis, i.e., OSF). Objective textural descriptors, namely discrete wavelet transform, gray-level co-occurrence matrix (GLCM), and local binary pattern (LBP), were extracted and fed to standard classifiers. Best classification accuracy of 87.28 and 93.21%; sensitivity of 93 and 96%; specificity of 80 and 91% were achieved, respectively, for SEM and AFM. In the study groups, SEM analysis showed a significant (p < 0.01) variation for all the considered textural descriptors, while for AFM, a remarkable alteration (p < 0.01) was only found in GLCM and LBP. Interestingly, sub-epithelial collagen nanoscale and microscale textural information from AFM and LM images, respectively, were complementary, namely microlevel contrast was more in normal (0.251) than OSF (0.193), while nanolevel contrast was more in OSF (0.283) than normal (0.204). This work, thus, illustrated differential micro-nano-textural attributes for oral epithelium and sub-epithelium to distinguish OPMD precisely and may be contributory in early cancer diagnostics.

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Fiber alignment drives changes in architectural and mechanical features in collagen matrices

Cited by 105 publications

References 39 publications

Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

Stromal Cells Promote Neovascular Invasion Across Tissue Interfaces

Elucidation of Differential Nano-Textural Attributes for Normal Oral Mucosa and Pre-Cancer

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