Exploring cellular changes in ruptured human quadriceps tendons at single‐cell resolution
The Journal of Physiology, vol. 603, pp. 4535–4554
Abstract
Tendon ruptures in humans have often been studied during the chronic phase of injury, particularly in the context of rotator cuff disease. However, the early response to acute tendon ruptures remains less investigated. Quadriceps tendons, which require prompt surgical treatment, offer a model to investigate this early response. Therefore, this study aimed to explore the early cellular changes in ruptured compared to healthy human quadriceps tendons. Quadriceps tendon samples were collected from patients undergoing fracture repair (healthy) or tendon repair surgery (collected 7-8 days post-injury). Nuclei were isolated for single-nucleus RNA sequencing, and comprehensive transcriptomic analysis was conducted. The transcriptomes of 12,808 nuclei (7268 from healthy and 5540 from ruptured quadriceps tendons) were profiled, revealing 12 major cell types and several cell subtypes and states. Rupture samples showed increased expression of genes related to extracellular matrix organisation and cell cycle signalling, and a decrease in expression of genes in lipid metabolism pathways. These changes were predominantly driven by gene expression changes in the fibroblast, vascular endothelial cell (VEC), mural cell, and macrophage populations: fibroblasts shift to an activated phenotype upon rupture and there is an increase in the proportion of capillary and dividing VECs. A diverse immune environment was observed, with a shift from homeostatic to activated macrophages following rupture. Cell-cell interactions increased in number and diversity in rupture, and primarily involved fibroblast and VEC populations. Collectively, this transcriptomic analysis suggests that fibroblasts and endothelial cells are key orchestrators of the early injury response within ruptured quadriceps tendon. KEY POINTS: Tendon ruptures in humans have regularly been studied during the chronic phase of injury, but less is known about the early injury response after acute tendon ruptures. This study explored the early cellular changes in ruptured compared to healthy human quadriceps tendons at single-cell resolution. Fibroblasts and endothelial cells seem to be the key orchestrators of the early injury response within ruptured quadriceps tendon. Therefore, these cell types are obvious targets for interventions to enhance tendon healing. Overall, this study highlights that the development of more effective therapeutic options for tendon injury requires better understanding of the cellular, extracellular, and mechanical landscape of tendon tissue.
Authors 15
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Jolet Y. Mimpen corresponding
University of Oxford · Kennedy Institute of Rheumatology
Affiliation as printed
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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University of Oxford · MRC Weatherall Institute of Molecular Medicine
Affiliation as printed
Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine University of Oxford Oxford UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden University, Leiden, the Netherlands
Leiden University Medical Center Leiden University Leiden the Netherlands
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford University Hospital NHS Foundation Trust, Oxford, UK
Oxford University Hospital NHS Foundation Trust Oxford UK
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Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford University Hospital NHS Foundation Trust, Oxford, UK
Oxford University Hospital NHS Foundation Trust Oxford UK
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford University Hospital NHS Foundation Trust, Oxford, UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Oxford University Hospital NHS Foundation Trust Oxford UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford University Hospital NHS Foundation Trust, Oxford, UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Oxford University Hospital NHS Foundation Trust Oxford UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
Oxford Centre for Translational Myeloma Research University of Oxford, Oxford, UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Oxford Centre for Translational Myeloma Research University of Oxford Oxford UK
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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Affiliation as printed
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK
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