The Interfascicular Matrix of Energy Storing Tendons Houses Heterogenous Cell Populations Disproportionately Affected by Aging.
Abstract: Energy storing tendons such as the human Achilles and equine superficial digital flexor tendon (SDFT) are prone to injury, with incidence increasing with aging, peaking in the 5 decade of life in the human Achilles tendon. The interfascicular matrix (IFM), which binds tendon fascicles, plays a key role in energy storing tendon mechanics, and aging 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 aging. 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 aging, with differential expression of genes related to senescence, dysregulated proteostasis and inflammation. This is the first study to establish heterogeneity in IFM cell populations, and to identify age-related alterations specific to IFM-localised cells.
Publication Date: 2023-05-22 PubMed ID: 37307816DOI: 10.14336/AD.2023.0425-1Google Scholar: Lookup
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- Journal Article
Summary
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This research focuses on understanding the cellular make-up of the interfascicular matrix (IFM) in energy-storing tendons, such as the human Achilles tendon, and how aging affects these cells, ultimately leading to increased risk of injury.
Interfascicular Matrix and Its Role in Tendon Mechanics
- The study attempts to understand the biological role of IFM, a structure that binds tendon fascicles in energy-storing tendons.
- The mechanical role of IFM in tendon functioning is established, but its biological function in relation to the resident cell populations is unknown.
- Energy-storing tendons, like the human Achilles tendon, are prone to injury, with the risk getting worse as people age.
- Changes in the IFM due to aging negatively impact tendon function, thereby making it crucial to understand the biological role of IFM-resident cells.
Identifying IFM-resident Cell Populations
- Cells from young and old equine superficial digital flexor tendons were analysed using single cell RNA-sequencing.
- The study aimed to identify how aging affects cell populations in the IFM structure by comparing the RNA sequences between young and old cells.
- Markers of each resulting cell population were used for immunolabelling to locate cell clusters in the structure.
- The research managed to identify eleven cell clusters, including tenocytes, endothelial cells, mural cells, and immune cells.
Age-related Changes in IFM-localised Cells
- One tenocyte cluster was found localised to the fascicular matrix, while the other nine clusters were localised to the IFM.
- The study showed that IFM-localised tenocytes and mural cells were particularly affected by aging.
- These cells displayed differential expression of genes related to senescence, dysregulated proteostasis and inflammation, all of which are functions impacted by the aging process.
- This study is the first to identify heterogeneity in IFM cell populations and to pinpoint age-related changes specific to IFM-localised cells.
Significance of the Study
- This understanding can significantly contribute to the study of tendon injuries and age-related tendon diseases.
- Future therapies targeting these areas could be potentially optimised to protect tendons from age-associated damages.
Cite This Article
APA
Zamboulis DE, Marr N, Lenzi L, Birch HL, Screen HRC, Clegg PD, Thorpe CT.
(2023).
The Interfascicular Matrix of Energy Storing Tendons Houses Heterogenous Cell Populations Disproportionately Affected by Aging.
Aging Dis.
https://doi.org/10.14336/AD.2023.0425-1 Publication
Researcher Affiliations
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK.
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK.
- Centre for Genomic Research, University of Liverpool, Liverpool, L69 7ZB, UK.
- Department of Orthopaedics and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital, Stanmore, HA7 4LP, UK.
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, UK.
- Department of Musculoskeletal and AgingScience, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK.
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK.
Citations
This article has been cited 10 times.- Sabatelli P, Di Martino A, Faldini C, Bonaldo P, Merlini L, Cenni V. Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential. Int J Mol Sci 2025 Dec 13;26(24).
- Iwasaki N, Llewellyn J, Brown J, Zamboulis DE, Finding EJT, Wheeler-Jones CPD, Thorpe CT. Immunolabelling and Micro-Computed Tomography Revealed Age-Related Alterations in 3D Microvasculature of Tendons. Aging Cell 2026 Jan;25(1):e70293.
- Najeb M, Samy A, Rizk A, Mosbah E, Karrouf G. Regenerative biologics modulating inflammation and promoting tenogenesis in equine superficial digital flexor tendonitis: from molecular pathways to clinical translation. Ir Vet J 2025 Sep 17;78(1):21.
- Gögele C, Pattappa G, Tempfer H, Docheva D, Schulze-Tanzil G. Tendon mechanobiology in the context of tendon biofabrication. Front Bioeng Biotechnol 2025;13:1560025.
- Li X, Fang L, Zhou R, Yao L, Clayton SW, Muscat S, Kamm DR, Wang C, Liu CJ, Qin L, Tower RJ, Karner CM, Guilak F, Tang SY, Loiselle AE, Meyer GA, Shen J. Current cutting-edge omics techniques on musculoskeletal tissues and diseases. Bone Res 2025 Jun 9;13(1):59.
- Møbjerg A, Pedersen SD, Kjaer M, Yeung CC. Role of the tendon circadian clock in tendinopathy and implications for therapeutics. Int J Exp Pathol 2025 May;106(3):e70001.
- Traweger A, Scott A, Kjaer M, Wezenbeek E, Scattone Silva R, Kennedy JG, Butler JJ, Gomez-Florit M, Gomes ME, Snedeker JG, Dakin SG, Wildemann B. Achilles tendinopathy. Nat Rev Dis Primers 2025 Mar 27;11(1):20.
- Guest DJ, Birch HL, Thorpe CT. A review of the equine suspensory ligament: Injury prone yet understudied. Equine Vet J 2025 Sep;57(5):1167-1182.
- Marr N, Meeson R, Piercy RJ, Hildyard JCW, Thorpe CT. Evaluation of suitable reference genes for qPCR normalisation of gene expression in a Achilles tendon injury model. PLoS One 2024;19(8):e0306678.
- Shojaee A. Equine tendon mechanical behaviour: Prospects for repair and regeneration applications. Vet Med Sci 2023 Sep;9(5):2053-2069.
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